COPD (chronic obstructive pulmonary disease) is a treatable and preventable disease state, characterized by progressive airflow limitation that is not fully reversible. It is a current and growing cause of mortality and morbidity worldwide, with the WHO (World Health Organization) projecting that total deaths attributed to COPD will increase by more than 30% in the next 10 years. The pathological hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the central airways (chronic bronchitis) and inflammation of the peripheral airways (respiratory bronchiolitis). The destructive changes and tissue remodelling observed in COPD are a result of complex interactions between cells of the innate and adaptive immune systems. The focus of the present review is directed towards the role of CD8+ T-lymphocytes, NK (natural killer) cells and NKT cells (NK T-cells). These three classes of killer cell could all play an important part in the pathogenesis of COPD. The observed damage to the pulmonary tissue could be caused in three ways: (i) direct cytotoxic effect against the lung epithelium mediated by the activities of perforin and granzymes, (ii) FasL (Fas ligand)-induced apoptosis and/or (iii) cytokine and chemokine release. The present review considers the role of these killer cells in COPD.

COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE): THE CLINICAL PROBLEM

COPD is a treatable and preventable disease state, characterized by progressive airflow limitation that is not fully reversible [1]. It is a current and growing cause of mortality and morbidity worldwide, with the WHO (World Health Organization) projecting that total deaths attributed to COPD will increase by more than 30% in the next 10 years [2].

Active smoking, as the predominant risk factor, is well established, although less than a quarter of smokers develop COPD and more than 15% of COPD occurs in never smokers, suggesting an important contribution of other factors, such as air pollution and other airborne irritants [3].

At present, the severity of the disease is assessed using spirometry, with additional information given by the BODE index [BMI (body mass index), dyspnoea and exercise tolerance; Table 1] [4]. The pathological hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the central airways (chronic bronchitis) and inflammation of the peripheral airways (respiratory bronchiolitis) [57] (Figure 1). Histopathological studies reveal that most inflammation in COPD occurs in the bronchioles and lung parenchyma. The bronchioles are obstructed by peribronchiolar fibrosis and there is destruction of lung parenchyma [5], which results in pulmonary emphysema. Although primarily a disease that affects the airways, COPD is increasingly recognized as a systemic disease and body mass alterations and endocrine disturbances have all been reported [810].

Table 1
COPD severity can be assessed using spirometry, BMI, dyspnoea and exercise tolerance, the BODE index score

FEV1, forced expiratory volume in 1 s

BODE index score
0123
FEV1 (% predicted) ≥65 50–64 36–49 ≤35 
Distance walked in 6 min (m) ≥350 250–349 150–249 ≤149 
MRC dyspnoea questionnaire 0–1 
BMI >21 ≤21   
BODE index score
0123
FEV1 (% predicted) ≥65 50–64 36–49 ≤35 
Distance walked in 6 min (m) ≥350 250–349 150–249 ≤149 
MRC dyspnoea questionnaire 0–1 
BMI >21 ≤21   

Representative images of the pathological hallmarks of COPD

Figure 1
Representative images of the pathological hallmarks of COPD
Figure 1
Representative images of the pathological hallmarks of COPD

The destructive changes and tissue remodelling observed in COPD are a result of complex interactions between cells of the innate and adaptive immune systems. However, the focus in the present review is directed towards the role of CD8+ T-lymphocytes, NK cells (natural killer cells) and NKT cells (NK T-cells).

Several studies have shown an increase in CD8+ T-lymphocytes within both the peripheral airways [5] and lower respiratory tract in patients with COPD [11,12], but this effect is less conclusive in peripheral blood, with some investigators reporting a decrease [12] and others no change [11,1316].

Circulating NK cells are decreased in smokers with COPD and have reduced phagocytic activity [17], and parallel changes in NK cells have been reported in normal smokers [18]. No difference in NK cell numbers or functional activity has been found in lung parenchyma of patients with COPD [19], although a decrease has been seen in the BAL (bronchoalveolar lavage) of patients with chronic bronchitis [20].

To date, no in-depth study of NKT cells in patients with COPD has been performed, although an increased number of Vα24-Vβ11 iNKT cells (invariant NTK cells) have been reported in asthma [21,22].

KILLER CELLS: PHENOTYPE AND FUNCTION

Many cells of both the innate and adaptive immune systems have the potential to kill. However, the present review will focus on the three main classes of human killer cells, which are heterogeneous and functionally distinct; namely, CD8+ T-lymphocytes, NK cells and NKT cells.

CD8+ T-lymphocytes originate from thymocytes, multipotent DN (double-negative) precursor cells for both αβ CD4+ and CD8+ T-cells, and γδ T-cells. The latter of which, although interesting due to their distinctive antigen recognition properties, are outside of the scope of this review. The predominant forms of these thymocytes express αβ TCRs (T-cell receptors) and, as they develop, they progress through three main stages defined by the differential expression of the CD4 and CD8 co-receptor molecules: CD4CD8 (DN), CD4+CD8+ [DP (double-positive)] and CD4+CD8 or CD4CD8+ [SP (single-positive)] (Figure 2). DP thymocytes first express a complete αβ TCR complex and undergo the processes of positive and negative selection based on their relative ability to interact with thymic-selecting ligands. Occurring in parallel with positive selection, and therefore difficult to disentangle experimentally, is the process of alternative commitment to cytotoxic or helper T-cell lineages, characterized by the respective down-modulation of CD4 or CD8 co-receptors. Commitment involves passage through a series of transitional stages with intermediate CD4 and CD8 expression, most notably the CD4+CD8lo stage, which includes progenitors of both the CD4 and CD8 lineages [2326]. Once committed, the resulting CD4+ Th (T-helper) cells and the CD8+ Tc (T-cytotoxic) cells differentiate further into either a type 1 (Th1 and Tc1) or type 2 (Th2 or Tc2) cell.

Development of SP T-cells in the thymus

Figure 2
Development of SP T-cells in the thymus

Following positive and negative selection, both SP CD4+ Th and CD8+ Tc cells differentiate further into either a type 1 or type 2 cell.

Figure 2
Development of SP T-cells in the thymus

Following positive and negative selection, both SP CD4+ Th and CD8+ Tc cells differentiate further into either a type 1 or type 2 cell.

One of the main immunological paradigms is that the pattern of cytokines, produced by activated T-lymphocytes, governs the qualitative and quantitative nature of immune responses. Type 1 T-cells secrete cytokines, such as IFN-γ (interferon-γ), crucial in the activation of macrophages and in the response to viral and bacterial infections [27,28], whereas type 2 T-cells secrete cytokines, such as IL (interleukin)-4, IL-5 and IL-13, involved in IgE-mediated responses and eosinophilia, and are characteristic of allergic diseases [29]. These cytokines can also modulate fibroblast proliferation and matrix production, which may result in tissue remodelling [30]. Several in vitro studies have demonstrated that type 1 and type 2 T-cells express distinct sets of chemokine receptors, which regulate the recruitment of these T-lymphocyte subsets to inflammatory sites [31,32]. In particular, it has been shown that the chemokine receptor CXCR3 is preferentially expressed on type 1 cells, which then selectively migrate towards its ligand CXCL10 [IP-10 (inducing protein-10)], expressed by lung epithelial cells [29,33,34]. This ligand has been shown to be up-regulated on lung epithelial cells when infected with rhinovirus, a common upper respiratory tract pathogen [34].

CD8+ T-lymphocytes cause lysis of target cells by two mechanisms: membranolysis, in which secreted molecules such as perforin and granzymes form pores in the membrane of target cells [35]; and apoptosis, mediated through the triggering of apoptosis-inducing (Fas-like) surface molecules on the target cell [36]. Both are dependent on ligation of the TCR by MHC class I–peptide complexes.

NK and NKT cells participate in innate immune responses [37,38] and contribute to combating intracellular pathogens [39]. Immune cells with NK cell markers can influence acquired immunity [40]. There are two distinct subsets of human NK cells identified by the cell-surface density of CD56 [NCAM (neural cell adhesion molecule)]. The majority (approx. 90%) of circulating NK cells are CD56dim and express high levels of FcγRIII (CD16), whereas a minority (approx. 10%) are CD56bright and CD16dim/neg (Figure 3). At sites of inflammation and in lymph nodes, however, CD56bright NK cells predominate. NK cells can activate Th1 cells by secreting IFN-γ or Th2 cells by secreting IL-4. The CD56bright subset has a lower cytotoxic potential, but are poised to secrete cytokines and are, therefore, regarded as immunoregulatory [4143]. Furthermore, the CD8+ subset of these CD56brightCD16 NK cells are thought to secrete Th2-type cytokines [44], which could have particular significance within the lung by skewing the microenvironment towards Th2/Tc2, as has been reported previously in COPD [16]. CD56dim plays a key role in natural and antibody-mediated cell cytotoxicity. The phylogeny and ontogeny of human NK cells are poorly understood, with comparative murine studies being greatly hindered by a lack of a CD56 homologue. Subset development models have therefore relied on in vitro studies, which have given rise to three possible models. First, a common precursor differentiates into either a CD56bright or CD56dim cell. Secondly, the subsets are capable of switching between forms and are governed by the microenvironment. Thirdly, one subset may be a precursor of the other. Supporting evidence has been documented for all three models [41,45,46].

Schematic representation of human NK CD56dim and CD56bright subsets, showing representative key differences

Figure 3
Schematic representation of human NK CD56dim and CD56bright subsets, showing representative key differences
Figure 3
Schematic representation of human NK CD56dim and CD56bright subsets, showing representative key differences

NKT cells have been classified as innate-like lymphocytes, which share features of both innate and adaptive immune cells [47]. NKT cells are a subset of T-cells that co-express an αβ TCR, of which most recognize lipid antigens presented on the MHC class I-like molecule CD1d [4851]. NKT cells share receptor structure and function with both NK cells and T-cells [52,53]. They can express T-cell membrane proteins, such as CD3, CD4 and CD8, and NK cell markers, including CD56, CD161 and inhibitory NK cell receptors [KIRs (killer Ig-like receptors)] [5255]. The immune regulatory role of NKT cells remains poorly defined, both for the overall NKT cell population and for the phenotypically different subtypes [56]. The most widely studied subset of NKT cells is that which recognizes the exogenous glycolipid antigen α-GalCer (α-galactosylceramide) through CD1d, a member of the family of non-polymorphic class I-like antigen-presenting molecules [57]. In humans, CD1d-dependent NKT cells generally express invariant Vα24 TCRs. Considerably less is known about the CD1d-independent NKT cells, but this subset expresses a non-biased TCR repertoire. When activated, NKT cells promptly secrete large amounts of cytokines [58], including IL-4 and IFN-γ. They can regulate immune responses in diverse situations, such as autoimmune diseases [59], tumour rejection [60] and different types of infections [61]. NKT cells are abundant among T-lymphocytes in the liver and bone marrow, are also found in the thymus and spleen, and are more frequent in pancreatic and mesenteric than other lymph nodes [62], although they are present in extremely low numbers in the peripheral blood [55].

Recent studies have highlighted the distinct Th1- and Th2-type cytokine profiles of NKT cell subpopulations [6367]. The CD4+CD8 NKT cells (CD4+ NKT cells) produce both Th1- and Th2-type cytokines [63,6567], and the CD4CD8+ (CD8+ NKT cells) and CD4CD8 NKT cells (DN NKT cells) produce predominantly Th1-type cytokines [6467]. The different cytokine profiles of NKT cell subpopulations suggest that these cells are likely to have different actions on different immune effector cells important in Th1- or Th2-type immune activities. This may contribute to the reported paradoxical functions of NKT cells.

The definition ‘NKT cell’ is not consistent, although recent reviews have tried to unify the terminology [50,6870]. As shown in Figure 4, CD56+CD3+ cells in humans are either CD1d-restricted or CD1d-independent. On the basis of the TCR expressed, CD1d-restricted T-cells, in turn, can be divided into subgroups of classical and non-classical NKT cells. CD1d-independent CD56+CD3+ T-cells may be called ‘NKT-like’ [50], with a final group named MAIT cells (mucosal-associated invariant T-cells) that are MR1-restricted [70,71]. MR1 is a β2m (β2-microglobulin)-dependent non-polymorphic MHC class I-like molecule encoded by a gene linked to the CD1d gene [70,71]. CD1d-restricted T-cells comprise a heterogeneous and functionally divergent population. A proportion of the cells in human express TCRs consisting of an invariant Vα24-JαQ TCRα chain combined with a Vβ11 TCRβ chain [48,57]. This subset is often referred to as iNKT cells or classical NKT cells (Figure 4). Cells with this family of TCRs can be activated by the synthetic ligand α-GalCer presented on CD1d-loaded tetramers [72]. A lysosomal glycosphingolipid was identified as an endogenous ligand for iNKT cells [73]. The CD1d-restricted cells not using the Vα24 invariant TCR [7477] appear to share the main characteristic features of NKT cells, such as the expression of NK cell markers, rapid cytokine secretion upon activation and a memory surface phenotype [7780]. They are thought to express a relatively diverse TCR repertoire; however, this subset may also contain sets of cells with invariant receptors different from the Vα24 type [81]. CD1d-restricted cells, which do not use the Vα24 invariant TCR, are referred to as non-classical NKT cells (Figure 4). Non-classical NKT cells are not activated by α-GalCer [82,83], but other CD1d-restricted ligands have been identified for this group of NKT cells [84]. CD1d-restricted T-cells with diverse TCRs may be more frequent than the Vα24 iNKT subset in humans [8587], emphasizing the need for further analysis of this subset. MR1-restricted MAIT cells have been researched less thoroughly than classical iNKT cells, although, due to their presence in mucosal sites of the gut and lung [71,8890], they could be of great interest in COPD. These cells express TCRs consisting of an invariant Vα7.2-Jα33 TCRα chain, which is predominantly combined with either a Vβ13 or a Vβ2 TCRβ chain [70,91] (Figure 4). Findings have postulated that α-ManCer (α-mannosylceramide) can activate these cells [9294].

Schematic representation of the subsets of human NKT cells

Figure 4
Schematic representation of the subsets of human NKT cells
Figure 4
Schematic representation of the subsets of human NKT cells

KILLER CELLS IN COPD: THE CURRENT STATUS

The three main classes of killer cell discussed in the present review could all play an important part in the pathogenesis of COPD, although their specific contributions have yet to be established. The observed damage to the pulmonary tissue could be caused in three ways. A direct cytotoxic effect against the lung epithelium mediated by the activities of perforin and granzymes [9598] and/or FasL (Fas ligand)-induced apoptosis [27,99]. Cytokine and chemokine release could either induce changes within the lung epithelial cells or activate and recruit other inflammatory cells to the lung.

A type 1 profile has been hypothesized in COPD, particularly because viral and/or bacterial infections are associated with the development of the disease [27,28]. This phenotype has been demonstrated in the peripheral blood of subjects with COPD [15], and others have also described it in bronchial biopsies of patients with COPD [100]. However, two recent studies have shown a type 2 profile in BAL [16,101], suggesting that there is intra-compartment variability within the disease.

As described previously, an increased number of CD8+ T-lymphocytes have been consistently identified in both the lower and upper respiratory tract of patients with COPD, although results have been less conclusive in peripheral blood. In-depth studies investigating the presence or absence of NK and NKT cells in either the lung or peripheral blood have not been completed, although our own findings suggest that both are reduced in number in the peripheral blood of smokers with COPD (R. A. Urbanowicz, J. R. Lamb, H. F. Sewell, I. Todd, J. Corne and L. Fairclough, unpublished results). In a further analysis of their potential effector functions, we failed to detect any differences in cytokine production; however, the cytolytic activity of the cells in an in vitro assay was significantly reduced (Table 2). This outcome may be the result of either selective recruitment into the lung or a systemic suppression of number and cytotoxic function.

Table 2
Representative peripheral results suggesting a decrease in the proportion and cytolytic ability of both NK and NKT cells in COPD

Findings from R. A. Urbanowicz, J. R. Lamb, H. F. Sewell, I. Todd, J. Corne and L. Fairclough, unpublished results.

Healthy participantsHealthy smokersSmokers with COPD
Killer cellProportion of cells (%)Cytotoxic ability (%)Proportion of cells (%)Cytotoxic ability (%)Proportion of cells (%)Cytotoxic ability (%)
NK cells (CD3CD56+60–75 45–60 0–30 
NKT cells (CD3+CD56+60–75 2.5 45–60 0.5 0–30 
Healthy participantsHealthy smokersSmokers with COPD
Killer cellProportion of cells (%)Cytotoxic ability (%)Proportion of cells (%)Cytotoxic ability (%)Proportion of cells (%)Cytotoxic ability (%)
NK cells (CD3CD56+60–75 45–60 0–30 
NKT cells (CD3+CD56+60–75 2.5 45–60 0.5 0–30 

The abilities of all three killer cells to cause direct damage to the lung epithelium and to recruit other cells of the immune system into the lung indicate their crucial role in driving the pathogenesis of COPD and should, therefore, be studied in much greater detail.

Abbreviations

     
  • BAL

    bronchoalveolar lavage

  •  
  • BMI

    body mass index

  •  
  • BODE

    BMI, dyspnoea and exercise tolerance

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • DN

    double-negative

  •  
  • DP

    double-positive

  •  
  • α-GalCer

    α-galactosylceramide

  •  
  • IFN-γ

    interferon-γ

  •  
  • IL

    interleukin

  •  
  • MAIT cell

    mucosal-associated invariant T-cell

  •  
  • NK cell

    natural killer cell

  •  
  • NKT cell

    NK T-cell

  •  
  • iNKT cell

    invariant NKT cell

  •  
  • SP

    single-positive

  •  
  • Tc

    T-cytotoxic

  •  
  • TCR

    T-cell receptor

  •  
  • Th

    T-helper

R. A. U. was funded by a GlaxoSmithKline PhD studentship.

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Author notes

1

The authors contributed equally to this work.