Abstract

The innate immunity is frequently accepted as a first line of relatively primitive defense interfering with the pathogen invasion until the mechanisms of ‘privileged’ adaptive immunity with the production of antibodies and activation of cytotoxic lymphocytes ‘steal the show’. Recent advancements on the molecular and cellular levels have shaken the traditional view of adaptive and innate immunity. The innate immune memory or ‘trained immunity’ based on metabolic changes and epigenetic reprogramming is a complementary process insuring adaptation of host defense to previous infections.

Innate immune cells are able to recognize large number of pathogen- or danger- associated molecular patterns (PAMPs and DAMPs) to behave in a highly specific manner and regulate adaptive immune responses. Innate lymphoid cells (ILC1, ILC2, ILC3) and NK cells express transcription factors and cytokines related to subsets of T helper cells (Th1, Th2, Th17). On the other hand, T and B lymphocytes exhibit functional properties traditionally attributed to innate immunity such as phagocytosis or production of tissue remodeling growth factors. They are also able to benefit from the information provided by pattern recognition receptors (PRRs), e.g. γδT lymphocytes use T-cell receptor (TCR) in a manner close to PRR recognition. Innate B cells represent another example of limited combinational diversity usage participating in various innate responses. In the view of current knowledge, the traditional black and white classification of immune mechanisms as either innate or an adaptive needs to be adjusted and many shades of gray need to be included.

Introduction

The concept of innate (non-specific) and adaptive (specific) immunity originates from historical disputes of Paul Ehrlich and Ilya Metchnikoff whether antibody-mediated or cellular responses are more important and is widely accepted for approximately 100 years [1]. Recent advancements in our understanding of immune mechanisms on the molecular and cellular levels contributed to a fall of several traditional dogmas leaving the border between the adaptive (lymphocyte dependent) and innate immunity (phagocytes, innate lymphoid cells (ILCs)) quite unclear. There are several lines of evidence showing that innate immune cells may gain some of the privileged functions previously attributed only to the adaptive immunity and that they are also vital for regulation of all the phases of adaptive immune responses. On the other hand, both T and B lymphocytes fulfill many functions which are not antigen-specific. Is there already the right time to leave this obviously simplistic concept?

Adaptive innate immunity

Innate immunological memory—training of innate immunity

Adaptation to environmental stimuli including induced enhancement to repeated responses against potentially harmful microorganisms is one of the features of all living organisms. Protection of plants against bacteria is fostered by memorizing previous infections and by induction of epigenetic changes leading to a so-called systemic acquired resistance (SAR) which enables more effective responses to future attacks [2]. In Bacteria and Archaea, CRISPR (clustered regularly interspaced short palindromic repeats) pathway based on retaining fragments of previously experienced viral DNA [3] can increase resistance in the case of reinfection. In primitive multicellular organisms like corals, presensitization leads to a stronger alloresponse as a result of parabiotic incompatibility [4].

Immunological memory may be characterized as a capacity of immune system to respond faster and more efficiently to an antigen after its consequent exposition. Formation of memory T and B cells is an undisputed framework for the antigen-specific secondary immune response and one of the traditional characteristics of adaptive immunity. On the other hand, experimental data from early 60s clearly documented that certain infections might also induce significant resistance to unrelated microorganisms and this phenomenon was linked to the modulation of host macrophages [5]. In addition to in vitro experiments, epidemiological data confirmed that African children with BCG scar and positive tuberculin reaction had better survival in areas with high overall mortality [6]. A non-specific immune-stimulation facilitated by BCG vaccine was shown to affect the response to major infections including malaria also in other parts of the world [7]. In this respect, the concept of innate immune memory, recently renamed to ‘trained immunity’, has attracted well-deserved interest [8].

Memory of mononuclear phagocytes

It has been clearly documented that monocytes pre-exposed to Candida albicans or β-glucans derived from their cell wall undergo functional reprogramming associated with up-regulation of pro-inflammatory cytokines TNF-α and IL-6 upon the re-stimulation and this effect involves epigenetic changes [9].

One of the characteristic features of β-glucan-trained monocytes is their metabolic switch from oxidative phosphorylation toward aerobic glycolysis (so-called Warburg effect) which depends on the activation of mammalian target of rapamycin (mTOR) through a dectin-1/Akt/HIF1α pathway [10]. Fumarate and other glycolytic metabolites, glutaminolysis and also cholesterol synthesis pathway are then responsible for epigenetic changes such as histone modifications (Figure 1), e.g. specific trimethylation of H3K4 (H3K4me) and acetylation of H3K27 (H3K27Ac), which lead to up-regulation of TNF-α and IL-6 production in monocytes re-stimulated with β-glucan [11]. Analogous epigenetic processes are important also for the induction of increased amplitude during classical adaptive immune memory by regulation of cell proliferation and clonal expansion of lymphocytes [12]. In mononuclear phagocytes, robust transcriptional response to stimulation in β-glucan-trained cells seems to be regulated by long non-coding RNAs [13]. The process is not exclusively pro-inflammatory, since β-glucan training simultaneously up-regulates the production of anti-inflammatory cytokines IL-10 and IL-1Ra and is highly dependent on duration of stimulation and requires sufficient resting time before the re-stimulation [14].

Immunological memory is not an exclusive property of adaptive immune responses

Figure 1
Immunological memory is not an exclusive property of adaptive immune responses

In addition to proliferation of antigen-specific T and B lymphocytes generated from memory cells, the capacity to respond faster and more efficiently to an antigen re-exposure may be also associated with metabolic and epigenetic reprogramming of monocytes and other innate immune cells. In NK cells, proliferation of reprogrammed cells is involved.

Figure 1
Immunological memory is not an exclusive property of adaptive immune responses

In addition to proliferation of antigen-specific T and B lymphocytes generated from memory cells, the capacity to respond faster and more efficiently to an antigen re-exposure may be also associated with metabolic and epigenetic reprogramming of monocytes and other innate immune cells. In NK cells, proliferation of reprogrammed cells is involved.

Epigenetic reprogramming of monocytes together with up-regulation of IL-1β was not shown only in experimental models, but was also documented in a human randomized placebo-controlled challenge study. In this case, BCG vaccination was applied to healthy volunteers 1 month before a yellow fever vaccine (a model of mild viral infection) and reduced viremia in correlation with increased IL-1β production [15]. IL-1β is a pleiotropic cytokine with multiple effects on immune and non-immune cells [16,17] and its role has also been previously studied in relationship with trained immunity [18]. In an experimental model of Pseudomonas aeruginosa infection, prophylactic administration of low doses of recombinant IL-1 increased natural resistance and prevented death in granulocytopenic mice [19]. Similar protective effects were shown also for infection by C. albicans [20]. Low doses of IL-1 protected mice also against cerebral malaria but this effect was reversed by administration of TNFα and did not occur in nude mice suggesting at least partial role of T lymphocytes [21].

A relatively short lifespan of most innate immune cells may represent an important innate memory limitation, although donor-specific alveolar macrophages persist in transplanted lung without being replaced by recipient’s cells for several years [22]. On the other hand, it has been shown that β-glucan-induced trained immunity is not limited only to mature myeloid cells but affects also myeloid progenitors making them more sensitive to a secondary challenge [23]. This mechanism may explain prolonged non-specific protective effect of some vaccines.

Memory of ILCs

The mononuclear phagocytes are not the only innate immune cells with memory characteristics. Non-specific protective effects of BCG on human volunteers may be also partially explained by enhanced production of proinflammatory cytokines, particularly IL-1β, by NK cells stimulated after 2 weeks and 3 months from original vaccination in vitro with either Mycobacterium tuberculosis sonicate, C. albicans blastoconidia or heat-killed Staphylococcus aureus [24]. It has been proposed, based on CMV infection data, that human memory (or memory-like) NK cells are characterized by CD57+NKG2Chi phenotypic pattern [25]. Percentage of these cells is increased during CMV reactivation or following hematopoietic stem cell transplantation into CMV positive recipient. NKG2C positive NK cells also respond to reactivation by enhanced production of IFNγ [26]. Memory-like characteristics of NK cells associated with an enhanced perforin synthesis can be obtained also by priming with leukemia cells [27]. Also the cytokine stimulation of human NK cells with combination of IL-12, IL-15 and IL-18 is associated with higher proliferation and IFNγ production upon re-stimulation with cytokines or interactions with K562 cells [28]. Adoptive transfer of human IL-12/15/18-preactivated NK in a xenograft melanoma mouse model showed more efficient rejection of tumors. It was demonstrated that long-term competence of NK cells to produce IFNγ is dependent on IL-2 [29]. Memory-like NK cells could be obtained alternatively using tetravalent bispecific antibody against CD30/CD16A, where CD16A engagement potentiated proliferative and cytotoxic responses to restimulation by cytokines and tumor cells [30]. In addition to NK cells, other populations of newly re-classified ILCs [31] are obvious candidates for remembering previous insults and stimuli. For mouse ILC1 cells was shown, that hapten-specific memory depend on lymph node-liver axis, IL-7Rα positive memory ILC1 cells being recruited to liver via CXCR6 [32]. In another mouse model, a memory-like subset of ILC2 cells induced by IL-33 producing IL-10 may play a role both in the induction and resolution of allergic inflammation [33]. Whether ILC3 subset, crucial cell population involved in fibrogenesis [34], is endowed with immunological memory has to be elucidated, yet.

Memory of parenchymal cells

By using an experimental model of imiquimod (a TLR7/8 agonist)-induced skin inflammation, a capability to respond more rapidly to a secondary assault was documented in epithelial stem cells. In this cell type activator of inflammasome AIM2 (Absent in melanoma 2) and its downstream effectors caspase-1 and IL-1β are the central regulators of the augmented wound repair [35].

Recently, characteristic metabolic and epigenetic changes resembling trained immunity wer also shown in smooth muscle cells stimulated with oxLDL and BCG, including increased glucose consumption, lactate production, responsiveness to 6-fluoromevalonate and mevalonate treatment and also inhibition of priming by the histone methyltransferase inhibitor [36]. In this respect, the concept that if not all, at least majority of the cell types can memorize previous microbial encounters [37] and perhaps other inflammatory stimuli sounds quite reasonable.

Innate tolerance and immunosuppressive training

Innate tolerance after LPS pretreatment via silencing of inflammatory genes has been previously shown. This is due to a mechanism, which is IL-1 dependent and inhibits NFκB and AP-1 activation [38]. The molecular mechanisms behind LPS tolerance have not been fully elucidated, yet but involve CD14/TLR4 signaling [39], microRNAs [40], chromatin modification and epigenetic reprogramming in macrophages [41]. Recent clinical studies with human volunteers have shown that LPS tolerance can be reversed by administration of β-glucan [42] or acetylsalicylic acid treatment [43].

Innate immunological memory/trained immunity in pathophysiology

The capacity of innate immune cells to respond vigorously to repeated stimuli is highly beneficial for protection against microbial pathogens but could also be involved in the amplification of immune responses in chronic inflammatory diseases where activated mononuclear phagocytes are present. In addition to multiple autoimmune and autoinflammatory diseases [44], metabolic and epigenetic reprogramming of macrophages may explain the mechanisms by which diabetes increases the risk of cardiovascular diseases [45].

Specificity of innate immune responses

In adaptive immune responses, e.g. generation of highly diverse B-cell receptor (BCR) and T-cell receptor (TCR) repertoires by somatic DNA rearrangements and mutagenesis enables both T and B lymphocytes to recognize incredible number of distinct antigens and unique epitopes. Until the discovery of TLRs (Toll-like receptors), the response of innate immune cells to environmental stimuli was considered being rather non-specific and antigen-independent. Extensive research in the field of pattern recognition receptors (PRRs) binding pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) have changed our view to much more sophisticated picture of antigen recognition by innate immune cells. The major groups of PRRs are traditionally classified into TLRs, NOD (nucleotide binding and oligomerization domain)-like receptors (NLRs), retinoic acid inducible gene-I-like receptors (RLRs), AIM2‐like receptors (ALRs), C-type lectin-like receptors (CLRs) and cytosolic DNA receptors (CDRs). These molecular sensors are localized in membranes (cytoplasmic or endolysosomal) and cytosol/nucleus and triggered co-operative intracellular signaling cascades [46] leading to activation of transcription factors and regulation of multiple genes.

TLRs as a first family of PRRs identified has been the most extensively studied. There are ten TLRs recognized in human and thirteen in mice, so far, expressed either on the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6, TLR10) or in the endosomes (TLR3, TLR4, TLR7, TLR8 and TLR9) (Table 1). In addition to monomeric forms, several TLRs, e.g. TLR1/TLR2 [47] or TLR4/TLR6 [48] may be expressed on the cell surface as preassembled signaling complexes. Endosomal TLRs are particularly important for detection of viral infections but may also provide other immunomodulatory functions in regulation of adaptive responses such as induction of memory cytotoxic T cells [49], inhibition of Th1 and Th17 development [50] or IL-12-dependent potentiation of Th1 responses [51] and B-cell activation and differentiation [52].

Table 1
TLRs represent one of the major families of PRRs used by immune cells for sensoring microbial motifs and molecular patterns of tissue injury
Receptor CD Location Major ligands Target 
TLR1 CD281 Plasma membrane Triacylated lipopeptides Bacteria 
TLR2 CD282 Plasma membrane Multiple glycolipids, lipopeptides and lipoproteins Bacteria, fungi 
TLR3 CD283 Endolysosomal compartment dsRNA Viruses 
TLR4 CD284 Plasma membrane LPS, HSPs, low-density lipoproteins Bacteria, endogenous proteins 
TLR5 CD285 Plasma membrane Flagellin, profilin Bacteria, Toxoplasma gondii 
TLR6 CD286 Plasma membrane Multiple diacylated lipopeptides, lipoteichoic acid, zymosan Bacteria, mycoplasma 
TLR7 CD287 Endolysosomal compartment ssRNA Viruses, bacteria, self RNA 
TLR8 CD288 Endolysosomal compartment ssRNA Viruses, bacteria, self RNA 
TLR9 CD289 Endolysosomal compartment Unmethylated CpG-containing DNA Bacteria, DNA viruses 
TLR10 CD290 Plasma membrane Unknown, dsRNA? Unknown 
Mouse TLR11 Gm287 Endolysosomal compartment Profilin T. gondii 
Mouse TLR12 Gm1365 Endolysosomal compartment Profilin T. gondii 
Mouse TLR13 Gm713 Endolysosomal compartment Bacterial ribosomal RNA Bacteria 
Receptor CD Location Major ligands Target 
TLR1 CD281 Plasma membrane Triacylated lipopeptides Bacteria 
TLR2 CD282 Plasma membrane Multiple glycolipids, lipopeptides and lipoproteins Bacteria, fungi 
TLR3 CD283 Endolysosomal compartment dsRNA Viruses 
TLR4 CD284 Plasma membrane LPS, HSPs, low-density lipoproteins Bacteria, endogenous proteins 
TLR5 CD285 Plasma membrane Flagellin, profilin Bacteria, Toxoplasma gondii 
TLR6 CD286 Plasma membrane Multiple diacylated lipopeptides, lipoteichoic acid, zymosan Bacteria, mycoplasma 
TLR7 CD287 Endolysosomal compartment ssRNA Viruses, bacteria, self RNA 
TLR8 CD288 Endolysosomal compartment ssRNA Viruses, bacteria, self RNA 
TLR9 CD289 Endolysosomal compartment Unmethylated CpG-containing DNA Bacteria, DNA viruses 
TLR10 CD290 Plasma membrane Unknown, dsRNA? Unknown 
Mouse TLR11 Gm287 Endolysosomal compartment Profilin T. gondii 
Mouse TLR12 Gm1365 Endolysosomal compartment Profilin T. gondii 
Mouse TLR13 Gm713 Endolysosomal compartment Bacterial ribosomal RNA Bacteria 

NLRs represent another important PRRs group of 22 well-conserved proteins scaffolding large signaling complexes through the formation of inflammasomes or directly activating NFkB and MAPK pathways [53]. The role of NLRs signaling in the activation of innate immune cells in response to viral or bacterial targets has been already well characterized but these receptors are important for the adaptive responses as well.

CIITA (class II major MHC transactivator), an NLR family member NLRA, is a central regulator of major histocompatibility complex (MHC) class II gene transcription [54] required for antigen-specific activation of Th lymphocytes by dendritic cells and macrophages. Similarly, NLRC5 plays a key role in the transcriptional regulation of MHC class I expression [55] consequently regulating activation of CD8+ cytotoxic lymphocytes and NK cells. There are also other mechanisms involved in NLRs regulation of adaptive responses such as promotion of thymocyte maturation [56], regulation of the CD8+ T-cell recruitment [57] or induction of IFNγ by Th1 cells [58]. Some of the NLRs may provide also immunosuppressive signals to inhibit NFκB pathway [59], caspase-1-mediated IL-1β processing [60] or IFN-γ responses [61].

RLRs recognize a wide variety of RNA viruses and play a key role in the controlled induction of type I IFNs by infected cells [62].

CLRs such as Dectin-1, Dectin-2, Mincle, mannose receptor and DC-SIGN are expressed particularly on myeloid cells. The traditional function of CLRs was to recognize fungal cell wall carbohydrates and initiate adaptive anti-fungal responses [63] but some of them such as DC-SIGN were shown to interact also with fucose-expressing extracellular pathogens to initiate protective Th2 responses [64]. Signaling via CLRs may be affected also by viruses inhibiting the type I IFN responses and thus down-regulating antiviral immunity [65].

CDRs are represented particularly by ALRs or cyclic GMP-AMP synthase and represent major factors in antimicrobial immune responses against cytosolic pathogens either by inflammasome formation [66] or regulation of interferons and other cytokines [67].

The number of pathogen-associated antigens recognized by PRR combinations on innate immune cells seems to be impressive but not fully comparable with that of recognized by T and B lymphocytes. On the other hand, an abundant proportion of these cells are equipped with specificities never used for the whole life or autoreactive. The cross-talk of signaling pathways triggered by the ligation of PRR is crucial for the decision of the antigen presenting cell, whether MHC molecules will present the antigen and thus whether helper or cytotoxic T-cell response will be activated. As an example, exposure of dendritic cells to TLR-4 and TLR-2 ligands leads to up-regulation of transcription factor EB (TFEB) which is responsible for lysosomal acidification together with protease expression and trafficking of MHC class II molecules to the cell surface to elicit helper T-cell responses [68]. On the other hand, activation of DC via TLR3, receptor for dsRNA, is associated with increased cross-presentation and leads to activation of CD8+ cytotoxic T lymphocytes and therefore strong anti-viral response [69]. In vertebrates, innate recognition by PRRs plays a key role particularly in the initiation the adaptive immune responses while in intervertebrates lacking T and B cells, the repertoire of PRRs is more than ten-fold higher, e.g. the sea urchin genome contains approximately 250 TLRs’ sequences, more than 200 NLRs and more than 1000 scavenger receptor cysteine-rich domains [70].

Self and non-self from the view of innate immunity

Another traditional and exclusive role of the adaptive immunity is to recognize and target foreign MHC antigens while tolerating own MHC molecules. Only NK cells expressing multiple inhibitory receptors for MHC-I had been accepted as an innate cell exhibiting self-tolerance (or self-reactivity) [71]. This view is in contrast with experimental data showing that intraperitoneal application of xenogeneic (pig) splenocytes into immunodeficient SCID mice lacking T cells and B cells elicited stronger neutrophil and macrophage responses than allogeneic or syngeneic cells. This result suggests that innate immune cells are capable of recognizing non-self patterns without the help of adaptive immune cells [72]. Direct evidence that monocytes respond to allogeneic non-self was then given in another study using T and B cell-deficient RAG−/− mice primed with allogeneic splenic cells or allogeneic tail skin graft in the conditions of NK cells and neutrophil depletion [73]. In a model of allogeneic induction of monocyte-derived dendritic cells, the recognition of non-self patterns requires the presence of the donor or host lymphoid cells (NK cells) producing IFNγ and seems to be independent of MHC antigens [74]. In this respect, the innate alloresponse may be triggered by a mismatch between other polymorphic membrane antigens as shown in the case of SIRPα/CD47 pathway [75] resembling allorecognition by stimulatory and inhibitory signals in NK cells.

Innate immune cells as regulators of adaptive immune responses

After the initiation of adaptive immune response by antigen presenting cells, the consequent differentiation of effector T cells is regulated by cytokines produced mostly by innate immune cells [76]. Importantly, differentiation of the Th1 lymphocytes inducing particularly responses against viruses and intracellular bacteria is controlled by IL-12 secreted by dendritic cells [77].

On the other hand, Th2 cells responsible for anti-helminth and allergic reactions are induced by IL-4, which is secreted by mast cells and ILC2 cells together with IL-33 and TSLP produced by stimulated epithelial cells [78].

For Th17 differentiation (associated with anti-fungal immunity and responses against extracellular bacteria), TGFβ and IL-6 are essential. Both cytokines could be secreted by multiple innate immune cells [79]. Additional two subsets of effector T helper cells, Th22 [80] and Th9 [81] are induced similarly by ’innate’ cytokines.

Also the differentiation of T regulatory cells, down-regulating immune reactions via cytokines IL-10 and TGFβ, is under the control of innate immunity. Moreover, ΝΚ cells represent an important source of IFNγ which is the main cytokine for activation of cytotoxic CD8+ T cells [82]. Finally, B-cell responses leading to the production of antibodies are regulated by several innate cytokines, e.g. IL-6 and BAFF [83,84].

If down-regulation of adaptive responses is needed, M2 macrophages together with myeloid-derived suppressor cells are involved [85,86].

It is obvious, that adaptive immune response as an evolutionary novelty could not be initiated and properly functional without the well-conserved ‘check points’ controlled by the innate immune cells.

ILCs—the missing link?

The discovery of new immune cell types with lymphocyte morphology but lacking the traditional membrane antigens and somatically recombined antigen receptors initiated an extensive research in the field which is just in between the innate and adaptive immunity (Figure 2). Initially, ILCs expressing Th2 cytokines (IL-4, IL-5, IL-13) were described in different tissues by several groups under different names: nuocytes [87], natural helper cells [88] or innate helper cells [89]. In addition to these ILC2 cells which also express Th2-specific transcription factor GATA3 [90], ILC1 cells with T-bet transcription factor and secreting IFNγ like (Th1 lymphocytes and NK cells) were described [91]. Furthermore, ILC3 subtype represents the population of cells with cytokines and transcription factors related to Th17 and Th22 cells [92]. There are still limited data on ILC regulatory cells which might be an innate alternative to T-regulatory cells producing anti-inflammatory cytokines IL-10 and TGFβ [93]. The similarities in effector mechanisms of cytotoxic T lymphocytes and NK cells (killing by perforins and granzymes) are already known for decades but recent data showed their conformity by showing induction of 200 same genes upon their activation during allograft rejection [94]. In the sense of evolutional biology, ILCs are not the ‘last common ancestor’ known by a non-scientific name the ‘missing link’ in the relationship of modern humans to the present anthropoid apes formulated by Charles Darwin and discussed up to present day [95], but might represent rather well-conserved defense mechanisms to backup relatively vulnerable T lymphocytes.

T lymphocytes and innate immune cells share quite similar transcription factors, cytokine profiles, and also effector functions in defense mechanisms and immunopathology

Innate immune responses in cells of the adaptive immune system

The hallmark cell types for adaptive immunity are T and B cells, both recombining/converting germ-line gene sequences into novel information, randomizing them to generate diversity of a magnitude to follow speed of the pathogen molecular evolution. Randomization step generating TCR and antibody binding diversity is linked to the selection of the rational variants in a context of the individual MHC allelic variants and gene polymorphism. From an evolutionary perspective, animal adaptive immunity emerged more than 500 million years ago with the complex morphology of vertebrates in at least two independent variants (as variable lymphocyte receptors – VLRs in jawless fish and TCR accompanied with Ig in jawed vertebrates) [87]. The first lymphoid cells could be first found in pre-vertebrate deuterostomes, obviously involved in non-adaptive functions. Some of the functions we identified for T and B cells in organisms with complex adaptive immune system could be traced to their putative original roles.

Phagocytosis

Textbook knowledge discriminates between lymphocytes and phagocytes (myeloid cells). The long-term paradigm that lymphocytes are non-phagocytic (and routinely used as a negative control in phagocytic assays) was challenged by the identification of the phagocytic B cells in early vertebrate animals [88]. Recently was shown that both T and B cells can phagocytose large objects including bacteria. As an example, murine B1 cells are able to kill phagocytosed bacteria, process them and present via MHC II to the CD4+ T cells [89]. Evo-devo functional plasticity between B cells and macrophages was proven, namely for mouse and human malignant B cell lines switching into macrophage-like phagocytic cells (‘lineage switching’), pointing to a particularly close relationship between myeloid lineage and B1 cells [96]. More surprising than for B cells (physiologically equipped with the MHC II presentation toolbox linked to the presentation of the endocytosed material) were reports indicating active phagocytic activity of T cells. More ‘innate’ T lymphocytes—γδT cells could actively phagocytose particulate material (e.g. Escherichia coli) and present bacterial antigens to αβ T lymphocytes [90]. Using T lymphoblastic leukemia lymphocytes (Jurkat) was shown, that also αβ T cells are able to phagocytose M. tuberculosis via micropinocytosis [92].

PAMP receptors on T and B cells

As mentioned above, TLRs play an essential role in the initiation of the innate immune responses and thereby also play crucial, although indirect, role in the induction of the consequent adaptive T-cell responses. Nevertheless, T cells also express unique TLR combinations functioning as co-stimulatory receptors supplementing TCR-induced signals to enhance T-cell effector behavior. The role of TLRs in T cell-mediated immune responses demands reconsideration of the paradigm that restricts germline-encoded pattern recognition to cells of the innate immune system [93,94]. Human peripheral blood T cells express mRNA for most TLRs, though with considerable variation in the reported expression levels among the studies. Protein expression of TLR2, 3, 4, 5 and 9 has also been detected by flow cytometry [97,98]. Interestingly, functional relevance of the pattern recognition in T cells is supported by the observation, that the TLR expression is regulated by TCR-dependent activation [80,99] and by the fact, that TLRs can serve as co-stimulatory receptors on T cells, where after ligation support TCR-mediated signals and co-stimulate cytokine production, proliferation and survival [81].

B cells also express almost complete set of TLRs, are equipped with relevant signaling machinery, therefore, could be highly activated after TLR ligation. Pattern recognition leads to pro-survival signaling in B cells, modulation of surface molecule expression, cytokine and antibody production accompanied by modified antigen presentation [45,100]. Similar to T cells, B cells can integrate signals through TLRs with the the B-cell antigen receptor and/or co-receptor CD40 orchestrating information important for both innate and adaptive immune functions of B lymphocytes [101]. Again, similar to T lymphocytes, TLR expression could be modulated by the antigen receptor ligation—e.g. TLR2 or TLR4 can be up-regulated on human B cells by cross-linking the BCR. Intimate signaling cross-talk between TLR4 a BCR in B cells was shown, where SYK kinase is mutually involved [102]. Functional participation of TLRs in B-cell biology seems to be developmentally regulated, since naïve human B cells express low levels of TLRs 1, 6, 7, 9 and 10, while activated and memory B cells show elevated TLR expression. Plasma cells express additional TLRs including TLR3 and TLR4 [103]. Furthermore, TLR4 expression and function are elevated in peripheral B cells from patients with inflammatory diseases [104].

Blurring the difference

The existence of exosomes, trogocytosis and nanotube-based membrane and cytosol intercellular exchange (Figure 3) could blur the cellular identity based on own translation and transcription regulation [105]. The fact, that cells can contain proteins and other molecules synthesized by another cell or even cell type could explain many interpretational caveats [106]. T and B cells could be doped by the ‘innate’ molecules, various cells could in opposite obtain adaptive receptors [107].

Blurring the difference between adaptive and innate cells is mediated by their intercellular transfer of membranes and cytosolic components either by exosomal exchange, nanotubes, or by trogocytosis

Exosomes

Exosomes (nanosized membranous vesicles 40–100 nm in diameter) are cell-derived extracellular vesicular structures containing various sets of cell type-specific protein and lipid components. Exosomes are mostly of an endosomal origin formed as inward budded intraluminal membranes within multivesicular bodies (MVB). T and B cells belong to the important exosome producers, expanding their functions to novel cellular territories. For example exosomes produced by FasL+ B cells positive for FasL and MHCII define population of the killer B lymphocytes with emerging role in regulation of the immune response and induction of tolerance [77]. Exosomes secreted by human T cells could act as vehicles delivering the miRNA to antigen-presenting cells (APCs) via immunological synapse. These exogenously transcribed RNAs could reprogram targeted cell, e.g. via miRNA-335 down-regulate translation of SOX-4 mRNA [78]. T and B cells can also receive exosomal cargo, including TLRs and ‘innate’ receptors and adhesion molecules [108].

Trogocytosis

Another example of synapse-dependent phenomenon in lymphocytes is a cell to cell membrane exchange called trogocytosis. The original observation involved CD8+ T cells as acceptors of the plasma membrane patches from APCs [79]. Since then, ability to share membrane components via trogocytosis was expanded to other cell types including CD4+ T cells, γδ T cells, B cells, NK cells, dendritic cells, monocytes or macrophages. Extensive evidence indicates that surface proteins are commonly transferred between immune cells in vitro and in vivo, and obviously this phenomenon is more general rule than an exception. Acquisition of APC derived cell surface MHCs and associated molecules by T cells endows them with novel functions and vice versa is true for APCs [109–111].

Nanotubes

Intercellular exchange through membrane tubes, long membrane protrusions between cells, provides another mechanism of transfer of the cell-surface proteome, intracellular signaling molecules and even organelles and pathogens between the cells [101]. Nanotubes formation has been observed in a wide range of immune cells, including B, T and NK cells, neutrophils, dendritic cells and monocytes, as well as glial and neuronal cells [105,106].

Functional consequences of exosomal, trogocytic or tunneling nanotube-mediated intercellular molecular exchange

Exosomes facilitate intercellular transfer of many signaling molecules, including receptors. Seminal paper for cancer biology [112] a decade ago demonstrated intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumor cells to bystander cells spreading the malignant phenotype. Since then was shown in various contexts (including immune cells), that exosomes could contain versatile molecular cargos such as nucleic acids (i.e. DNAs, mRNAs, microRNAs, many non-coding RNAs), proteins, lipids and metabolites, which is directly internalized by recipient cells, lead to their morphological and functional changes. The hypothesis, that intercellular transfer of microRNAs could modulate gene expression in acceptor cell was proven by unidirectional transfer of miR-335 loaded exosomes from T cells to APCs [113]. Transfer of functional receptor was shown among others for TLR-4 from bone marrow-derived dendritic cells to TLR4-knockout BMDCs accompanied by increase cellular responsiveness to LPS in recipient cells [114]. Exosomes are obviously key regulators of such central events in immunoregulation as establishment of central tolerance. For example, thymic exosomes (mostly derived by thymic epithelial cells acquired by thymocytes) promote final maturation of single positive CD4+CD25 cells into mature thymocytes with S1P1+Qa2+ and CCR7+Qa2+ phenotypes [115]. Antigens associated with the membranes of exosomes are presented at much higher efficiency than soluble antigens, and the natural adjuvant properties of exosomes are still poorly understood. Explanation involving several co-operating cell types was recently reported for primary B cell-derived exosomes, where dendritic cells are the exosome acceptors providing exosomal antigen cross-presentation and co- stimulatory machinery to or CD4 T cells, B cells and NK cells providing help for CD8 T cell-mediated response [116]. These and many more examples indicate the importance of extracellular vesicles in many immunoregulations and immune effector functions. The field of exosomal (extracellular vesicle) contribution to the immunoregulations was recently reviewed [117].

Trogocytic example, when cell after acquiring a membrane patch from another cell type can dramatically change functionality (through cell-surface molecules that they temporarily display but do not express themselves) is an uptake of immune-tolerogenic HLA-G (specifically HLA-G1) by some resting but most activated CD4 and CD8 T cells [118] which could serve as fast track to become a regulatory T cell. CD4+HLA-G1acq+ T cells change significantly their behavior—they no longer responded to proliferation stimuli and elicit regulatory function immediately after trogocytic acquisition of HLA-G. Trogocytosis of HLA-G1 might therefore enhance the ‘emergency’ immune suppression mechanism used by HLA-G-expressing tissues to protect themselves against immune attack. Another, but similar example involving transfer of HLA-G could explain rapid formation of tolerogenic NK cells in the HLA-G positive tumor microenvironment. Activated NK after acquisition of the HLA-G1 from tumor cells cells stop proliferation, loose cytotoxicity and start to behave as suppressor cells [119]. Important functional consequences could follow trogocytic acquisition of CD80 and CD86 which was demonstrated for iTregs from mature dendritic cells. Importantly, iTregs that acquired CD86 from mDCs expressed higher activation markers and their ability to suppress naive CD4(+) T-cell proliferation was enhanced [120]. Trogocytic intercellular transfer could explain non-classical expression patterns (without corresponding transcriptional evidence), like MHC II positivity in basophils potentially allowing them to function as APCs, matter of considerable controversy. It was clearly demonstrated, that it could be achieved by the acquisition of peptide–MHC-II complexes from dendritic cells via cell contact-dependent trogocytosis in vitro and in vivo and that the acquired complexes enable basophils to stimulate and differentiate T cells toward Th2 cells [121].

Novel concept of supercellularity based on the existence of the tuneling nanotubes (TNTs) is rapidly changing paradigms in many research areas. The fact, that cells could be interconnected by membrane tunnels (necessarily involving membrane fusion in between the distinct cells and consequent lateral movement of membrane components between the partners) with the transport function is dynamizing our notion about the dynamics and quantity of the intercellular transfers. Well-documented examples of mitochondrial transfer or hitchhiking by pathogens (HIV) or pathogenic protein aggregates (Huntingtin, prion) could work for immune cells as well. The conceptual breakthrough in understanding of prion transfer was based on the characterization of the dendritic cell involvement. It starts in the gut, where prion protein is acquired, continue to the lymph nodes and consequently via tunneling nanotubes to the neurons [122]. Membrane nanotubes could also facilitate long-distance interactions. It was shown that natural killer cells could use TNTs (the length could sometimes extend to >100 μm) for targeting cells, including their lysis [123]. The proof of principle that functionally important molecules could migrate between lymphocytes via TNTs was shown for H-Ras (also for CD86) transfer from B to T cell. The probable scenario is, that after formation of the tunneling nanotube regularly interchange organelles together with soluble and membrane proteins. Example of such transfer between the immune (in this case, leukemic B-cell precursor ALL) and non-immune cell (bone marrow-derived mesenchymal cells) was shown, when autophagosomes, mitochondria and the transmembrane protein ICAM1 were transferred toward MSCs [124]. This could help to reprogram stromal cells to the secretion of leukemic pro-survival cytokines. The emerging role of TNT in immune system was recently reviewed [125], with the emphasis on mechanisms of TNT formation and the reticulation of the dendritic cells enabling the intercellular transfer of antigens and MHC molecules.

γδT cells: innate adaptive immune cells?

Human γδT cells represent a minor population in the peripheral blood but constitute a major population among intestinal intraepithelial lymphocytes. Most γδT cells recognize ligands which are fundamentally different from short peptides that are seen by the conventional T cells in the context of MHC class I or class II molecules. As an example, human Vδ2 T cells recognize small bacterial phosphoantigens, alkylamines and synthetic aminobisphosphonates, whereas Vδ1 T cells recognize stress-inducible MHC-related molecules MICA/B as well as several other ligands [96]. As a response, activated γδT cells rapidly produce a variety of cytokines and usually exerts potent cytotoxic activity, mostly toward many tumor or stressed cells. γδT cells could be viewed as a bridge between the innate and the adaptive immune system (Figure 4) by using TCR as a PRR. In addition to pro- and anti-inflammatory cytokines, γδ T cells are a source of several growth factors and are essential for optimal wound healing [108,109]. In humans, γδ T cells produce transcripts and/or proteins for KGF (keratinocyte growth factor), insulin-like growth factor (IGF)-1, epidermal growth factor (EGF), fibroblast growth factor (FGF)-9, angiogenin (ANG), platelet-derived growth factor (PDGF) or VEGF. In a pathological context, e.g. within the tumor microenvironment γδ T cells could became critical drivers of tumor progression and metastasis, particularly via promotion of angiogenesis [110,111].

Human γδT cells are a bridge between the innate and the adaptive immune system

Figure 4
Human γδT cells are a bridge between the innate and the adaptive immune system

They use TCR as a PRR to recognize multiple ligands including antigens of stressed cells. In addition to a large scale of pro- and anti-inflammatory cytokines, γδ T cells represent an important source of growth factors which are essential for wound healing and angiogenesis. Finally, γδT cells may play a role in the systemic metabolic regulation.

Figure 4
Human γδT cells are a bridge between the innate and the adaptive immune system

They use TCR as a PRR to recognize multiple ligands including antigens of stressed cells. In addition to a large scale of pro- and anti-inflammatory cytokines, γδ T cells represent an important source of growth factors which are essential for wound healing and angiogenesis. Finally, γδT cells may play a role in the systemic metabolic regulation.

γδ T cells could play a role even in the systemic metabolic regulation. Unexpectedly, maintenance of core body temperature relies on adipose tissue-resident γδ17 T cells which accumulate with age and produce IL-17, which controls the homeostasis of regulatory T cells and adaptive thermogenesis via modulating activity and differentiation of brown and beige adipose tissue. Mice, where γδ T cells are absent, decrease ST2+ Treg cells and IL-33 in visceral adipose tissue—and lack the ability to regulate core body temperature at thermoneutrality and after cold challenge [82].

Innate-like B cells

Innate-like B cells (ILBs) are heterogeneous population of unconventional cells with B-cell markers endowed with innate sensing and responding characteristics. ILBs in mice are composed of relatively well-characterized B1 cells and marginal zone (MZ) B cells together with other B cell-like species, recently characterized as natural killer-like B cells, innate response activator (IRA) B cells, T-bet positive B cells, IL-17-producing B cells or human self-reactive VH4-34-expressing B cells [126].

The original definition of ILBs stressed the fact that their BCRs are semi-invariant or germline-encoded with limited diversity, indicating inherited biased functional combinatorics. Relatedly, antibodies generated by B1 and MZ B cells are typically polyreactive and autoreactive, with the capacity to recognize conserved structures across species. ILBs are most often the major source of natural antibodies under physiological circumstances; highly positive for IgM in combination with low IgD levels on their surfaces, simultaneously accompanied with defective BCR signaling after surface immunoglobulin cross-linking [127]. Stimulation (innate-like) via PAMP receptors leads to rapid activation of their effector function, e.g. TLR activation via microbial molecular patterns leads to the production of the large amount of natural antibodies (mainly IgM) providing quick and robust antimicrobial response or IL-10, a key regulatory cytokine with an important role in negative feedbacks modulating immune responses [128].

Within the transcriptional profile defining B-cell identity, separate subpopulation of innate B cells was recently identified in mice and in humans. Surprising combination of markers is exhibited by CD19+NK1.1+ NKB cells (obviously distinct from conventional NK and B cells) which reside mainly in the spleen and mesenteric lymph nodes. NKB cells express a limited diversity of germline-encoded BCR, are rapidly activated upon challenge with innate stimuli and subsequently produce large amounts of IL-18 and IL-12. These cytokines typically activate ILC1s and NK cells to initiate innate immunity against pathogens [129].

Another example are VH4-34-B cells expressing the germline Ig variable heavy chain 4-34 combination producing the autoantibodies that recognize I/i carbohydrates expressed by red blood cells and potentially cross-reactive with antigens present on commensal bacteria. This unique B-cell subpopulation may therefore represent an innate-like cellular armory specialized to control of commensal bacteria when gut (a generally mucosal) barriers are broken [83].

CD19+B220dimGL7CD138+ plasmablast-like B cells could serve as a major source of rapid, innate-like production of IL-17 in response to specific parasitic infection. These IL-17+ B cells could even outnumber the conventional inflammatory Th17 cells [84].

Another unique B-cell population is IRA B cells specifically producing GM-CSF. IRA B cells could differentiate in a PRR-dependent manner from B-1a in the mouse peritoneum and consequently accumulate in large numbers in the splenic red pulp. Rapid and potent GM-CSF production by IRA B cells could affect activity of other innate cell subsets, such as myeloid cells [86].

Traditionally, innate immunity was perceived as a set of relatively primitive forces responding to the pathogen invasion until the adaptive immunity is ready to solve the problem in a more sophisticated way. This concept is in many aspects in contradiction with current advancements in the field and it might be just time to start teaching our students that lymphocyte-mediated immune response with production of antibodies and generation of cytotoxic lymphocytes is only an excellent upgrade of original powerful immune programs being able to solve serious pathogen infestations. Similar to any upgrade, the relatively evolutionary young ‘adaptive’ (450 million years) as compared with ‘innate’ (1000 million years) immunity [102] has its bugs e.g. being much more susceptible to immunodeficiencies and immunopathological reactions. Obviously, the hyperinflammation due to exaggerated innate immune activation is also an important pathophysiological mechanism in autoimmune and particularly autoinflammatory diseases [130]. The profound lifestyle change in the last three decades had relatively limited effect of our phagocytes but exaggerated the regulation of Th1/Th2/Th17 responses and antigen specificity of ‘adaptive’ reactions. Since the precise rebuilding and rewiring of our immune responses to new environmental conditions may take naturally several thousand years, we should take more attention to the intimate interdependence with the innate responses to help relatively vulnerable ‘adaptive’ immunity to effectively adapt to the current world.

Concluding remarks

The textbook view of sharp distinction between innate and adaptive immunity, so efficient as a reductionist concept in the early times of the immunology, when relatively simple techniques were applied on an extreme complex humoral and cellular system is recently challenged by the application of OMICS unbiased methodologies together with the application of single cell analysis (namely single cell transcriptomics). The possibility to study individual cells in the population in the very detail in many aspects contradicts the averaging classical paradigm. More than the uniform troops of specialist, immune system cellularity resembles stochastic attempts to deal with unprecedented events. The classical sets of cell types get subcategorized, often pointing out cells in between the adaptive and innate immunity [131]. On the top of it, classical deterministic view (cells following a certain differentiation pathway) of the hematopoiesis is challenged by the alternative scenarios introducing stochasticity [132], or alternatives fitting better to the inter-lineage plasticity like myeloid-based model bringing to close proximity development of lymphoid and myeloid cells [133]. All abovementioned is fundamentally blurring the original sharp distinction, which should be viewed as a historical concept based on the lack of appropriate methodologies.

From the evolutionary point of view, billions of years of the host–pathogen interactions resulted in the consequent development of multiple orchestrated strategies how to recognize and eliminate the various parasites and response to the stress and damage. After (or even simultaneously) development specific and effective PAMPs and DAMPs, ‘temptation’ to memorize encounters with the particular invader led to the invention of introducing fragments of pathogens into its own genetic information (e.g. CRISPR/CAS-9) or epigenetically solidify already successful transcription programs (trained immunity). Morphological and functional ‘big bang’ (e.g. neural crest or derivatives of pharyngeal slits among others) inherent to the evolution of the chordates and bringing new gene regulatory opportunities offered ‘old immune system to learn new tricks’. The development of the DNA randomization steps, selection processes, presentation of antigens or antigen-specific lymphocytes is based on the use and evolution of already existing genes or cell types. It is therefore not surprising, that what is built on adaptive immune mechanisms would keep the evolutionary memories and inbetweeners would be part of the system, not the opposite. Even the evolution of the adaptive mechanisms seems to work anti-dogmatically, as was shown for recently described lymphocyte X bearing on the surface both T- and B-cell receptors [134].

On the top of above mentioned evo-devo aspects, existence of intercellular transfers of genetic material, organelles and obviously proteins including signaling molecules blur the potential difference even more. Based on the recent developments, it is credible to expect, that advances in the single cell analytical tools together with in vivo functional analyses and application of systems and quantitative immunological approaches on various animal models will diminish the distinction between the innate and adaptive mechanisms, most probably into semi-continuum with high degree of stochasticity and plasticity on the cellular level and under microenvironmental conditions.

Funding

This work was supported by the Ministry of Health, Czech Republic - Conceptual Development of Research Organization (‘Institute for Clinical and Experimental Medicine – IKEM, IN 00023001’) [grant number 15-26883A (to I.S.)].

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • AIM2

    absent in melanoma 2

  •  
  • ALR

    AIM2‐like receptor

  •  
  • AP-1

    activator protein 1

  •  
  • APC

    antigen-presenting cell

  •  
  • BAFF

    B-cell-activating factor of the tumour-necrosis-factor family

  •  
  • BCR

    B-cell receptor

  •  
  • CDR

    cytosolic DNA receptor

  •  
  • CLR

    C-type lectin-like receptor

  •  
  • CMV

    cytomegalovirus

  •  
  • CRISPR

    clustered regularly interspaced short palindromic repeats

  •  
  • DAMP

    danger-associated molecular pattern

  •  
  • DC-SIGN

    dendritic cell-specific ICAM-grabbing non-integrin

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • GM-CSF

    granulocyte-macrophage colony stimulating factor

  •  
  • HIF1

    hypoxia-inducible factor 1

  •  
  • ICAM-1

    intercellular adhesion molecule 1

  •  
  • IFNγ

    interferon gamma

  •  
  • IL

    interleukin

  •  
  • ILB

    innate-like B cell

  •  
  • ILC

    innate lymphoid cell

  •  
  • IRA

    innate response activator

  •  
  • iTreg

    induced T regulatory cell

  •  
  • LPS

    lipopolysaccharide

  •  
  • MHC

    major histocompatibility complex

  •  
  • MICA/B

    MHC class I chain-related protein A and B

  •  
  • MZ

    marginal zone

  •  
  • NF-κB

    nuclear factor kappa B

  •  
  • NLR

    NOD-like receptor

  •  
  • NOD

    nucleotide binding and oligomerization domain

  •  
  • oxLDL

    oxidized low-density lipoprotein

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PRR

    pattern recognition receptor

  •  
  • RAG

    recombination-activating gene

  •  
  • RLR

    retinoic acid inducible gene-I-like receptor

  •  
  • SOX-4

    SRY(sex determining region Y)-box transcription factor 4

  •  
  • SYK

    spleen tyrosine kinase

  •  
  • TCR

    T-cell receptor

  •  
  • TLR

    Toll-like receptor

  •  
  • TNT

    tuneling nanotube

  •  
  • TSLP

    thymic stromal lymphopoietin

  •  
  • VEGF

    vascular endothelial growth factor

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