CD8⁺ T Cell Subsets and Chronic Obstructive Pulmonary Disease

DAVID M. KEMENY, BEEJAL VYAS, MILICA VUKMANOVIC-STEJIC, MATTHEW J. THOMAS, ALISTAIR NOBLE, LI-CHER LOH, and BRIAN J. O'CONNOR

Guy's, King's, and St. Thomas's (GKT) School of Medicine, King's College, London, United Kingdom

	ABSTRACT

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AM J RESPIR CRIT CARE MED 1999;160:S33S37.COPD is a debilitating and progressive condition in which the airways become irreversibly obstructed and the lungs progressively damaged. Unlike asthma, we know little about the cells that initiate and drive this process. Research has shown that CD8⁺ T cells are overrepresented in the lungs of patients with COPD and that they are inversely related to lung function. However, not all CD8⁺ T cells are alike and subsets that make IFN- but not IL-4 (Tc1), IL-4 but not IFN- (Tc2) as well as those that make both (Tc0) have been described. This article focuses on the characteristics of CD8⁺ T cell subsets and considers their potential contribution to chronic obstructive pulmonary disease (COPD). Kemeny DM, Vyas B, Vukmanovic-Stejic M, Thomas M, Noble A, Loh LC, O'Connor BJ. CD8⁺ T cell subsets and chronic obstructive pulmonary disease.

	INTRODUCTION

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To facilitate gas exchange the respiratory tract is in intimate contact with the outside world. For this reason, unlike the skin, it cannot be covered with a tough outer cuticle and is, therefore, highly susceptible to infection. The immune system plays a vital role in protecting the respiratory mucosa from infection. In addition to fighting infection, immune responses in this vulnerable tissue must be tightly regulated to prevent collateral damage. For example, a vigorous immune response is necessary to clear viral or bacterial infection but the same immune cells that do so are capable of causing extensive tissue damage if they continue to be active (1). The cells that orchestrate this response are immune T cells. The respiratory mucosa contains large numbers of T cells and a network of dendritic cells that present antigen to them.

	THE DIVISION OF LABOR BETWEEN CD4+ AND CD8+ T CELLS

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CD8⁺ T cells are MHC class I restricted while CD4⁺ T cells respond to antigenic peptides presented in the MHC class II cleft. The MHC I pathway collects antigen present in the cytosol of the cell such as viral or self-proteins that have been broken down into small peptides by the proteasome. Soluble protein antigens enter the MHC class II pathway (Figure 1). However, these two pathways are not completely exclusive and when antigen-presenting cells, such as macrophages, are activated by binding to plastic, their ability to process soluble antigen via the MHC I pathway is greatly enhanced (Figure 2). Apart from MHC restriction there are other differences between CD4⁺ and CD8⁺ T cells and these are summarized in Table 1. CD4⁺ T cells survive better than CD8⁺ T cells in culture. This may in part explain why much more is known about CD4⁺ T cell biology, as CD8⁺ T cells are difficult to propogate. CD8⁺ T cells more readily undergo apoptosis in culture unless rescued by specific cytokines or other stimuli. However, CD8⁺ T cells are remarkably resistant to Fas-induced apoptosis. This is not surprising as CD8⁺ T cells are capable of high levels of Fas ligand expression and use this to induce apoptosis in other cells (2). Finally, the generation of CD8⁺ T cells that make IL-2 and proliferate is inhibited by moderate (20 U/ ml) concentrations of interleukin 4 (IL-4) and IL-2 (3).

View larger version (40K): [in this window] [in a new window]   Figure 1.   MHC class I and II antigen-processing pathways.

View larger version (29K): [in this window] [in a new window]   Figure 2.   Proliferation of CD8+ v5.2 TcR-transgenic T cells after culture with adherent splenic antigen-presenting cells pulsed with OVA peptide or whole ovalbumin. APC = antigen-presenting cell.

View this table: [in this window] [in a new window]   TABLE 1 DIFFERENCES BETWEEN CD4+ AND CD8+ T CELLS

	CD4+ T CELL SUBSETS

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Until 1986 it was unclear how the different effector functions of CD4⁺ T cells were organized. Different biological effects were mediated by specific T cells but the molecular mechanisms were unclear. All this was changed by an article published by Mosmann and coworkers in 1986 (4), in which they too classified a number of well-established mouse CD4⁺ T cell clones according to the cytokines they produced. They observed that the clones could be polarized into those that secreted interferon  (IFN-), IL-2, and tumor necrosis factor  (TNF-) but not IL-4, IL-5, IL-6, and IL-10 or p600 (IL-13), which they termed T helper 1 (Th1), and those that made IL-4, IL-5, IL-6, and IL-10 or p600 (IL-13) but not IFN-, IL-2, or TNF-, which they called T helper 2 (Th2). Some cytokines such as TNF-, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were produced in similar amounts by both cell types. It soon became evident that Th1 cells were associated with immunity to bacterial and viral pathogens while Th2 responses were associated with nematode and other parasitic infections and with IgE-mediated allergy and asthma. A third category termed Th0, which made all cytokines, was later described (5) and this has since been joined by Th3 cells that make TGF- (6) and Tr1 cells that mainly make IL-10 (7). These latter two types are believed to be involved in immune regulation.

Th2 cells can readily be found in the late-phase response both in the lung (8) and after intradermal injection of antigen into the skin (11). Some of the cytokines secreted by these cells have direct proinflammatory effects. Both IL-4 and IL-5, for example, promote the recruitment and survival of eosinophils and mast cells (12), while IL-6 causes lung inflammation IL-6-transgenic mice have a 20-fold increase in lung hyperresponsiveness (13, 14). Other cytokines made by both Th1 and Th2 cells, such as GM-CSF, contribute to lung inflammation by promoting monocyte activation and survival (15). Mice and rats sensitized with ovalbumin have increased airway responses to acetylcholine after ovalbumin aerosol challenge. T cells alone duplicate this after passive transfer of antigen-primed CD4⁺ T cells to naive animals (18, 19). The degree of hyperresponsiveness depends on the strength of the Th2 response and the presence of CD8⁺ T cells (20). Thus T cells alone can cause increased bronchial hyperresponsiveness in asthma.

In the lung Th1 responses are associated with infection with pathogenic organisms such as Mycobacterium tuberculosis (21, 22) and sarcoidosis (23). In addition to Th2 T cell- mediated pathology, Th1 cells, if unchecked, can cause inflammation and chronic tissue damage. Th1 cells induce neutrophil and macrophage infiltration and may promote granuloma formation.

CD8⁺ T cells are potentially damaging. This may explain why they are more prone to activation-induced cell death, although not to Fas-mediated apoptosis. After activation in vivo or in vitro with anti-CD3, CD8⁺ T cells are more likely to become apoptotic. Furthermore, when cultured with high concentrations of IL-4 or IL-2, CD8⁺ T cells become unresponsive and express lower levels of the IL-2R common  chain (3). Thus these CD8⁺ T cell responses tend to be self-limiting under normal circumstances.

	CD8+ T CELL SUBSETS

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For a number of years it was believed that the Th1/Th2 paradigm did not apply to CD8⁺ T cells. Most CD8⁺ T cells had a Th1 cytokine profile and these cells rarely seemed to produce IL-4 (5). In the early 1990s this view began to be challenged: first by the observation, by Seder and colleagues (24), that mouse CD8⁺ T cells cultured with IL-2 and IL-4 made significant amounts of IL-4; then, in patients with leprosy, where Salgame and coworkers showed that CD8⁺ T cells that made IL-4 were associated with the more severe lepromatous form of the disease and could inhibit Mycobacterium leprae-specific cytotoxic CD4⁺ T cells (25, 26). Indeed, CD8⁺ T cells from naive rats made more IL-4 than did CD4⁺ T cells when stimulated with phorbol myristate acetate (PMA) and ionomycin (27).

CD8⁺ T cells can differentiate into cells that make IFN- but no IL-4 (Tc1 cells) and cells that make IL-4 but not IFN- (Tc2 cells) (28, 29). However, it is difficult to produce mouse or rat Tc2 cells (27) from wild-type (i.e., not transgenic) animals or human Tc2 CD8⁺ T cell clones (30), although there are isolated reports of such cells obtained from the gingiva (31) and peritoneum (32). By using appropriate stimuli we have made mouse Tc1 and Tc2 cells (Figure 3) and human Tc1 and Tc2 cell clones. Unlike Th1 and Th2 CD4⁺ T cells, CD8⁺ T cell subsets appear to be equally cytolytic. However, the level of toxicity appears to depend on the level of peptide- MHC class I expression and possibly on the amount of costimulation. Furthermore, CD8⁺ T cell subsets respond differently to cytokines. IL-12 enhances Tc1 but not Tc2 cell growth while IL-4 inhibits Tc1 cell proliferation but has no effect on Tc2 cells. Finally, Tc1 and Tc2 cell clones differ in the level of cell surface antigens they express, although it is not clear at what stage of differentiation this takes place. In our hands, established human Tc1 CD8⁺ T cell clones express little CD30, CD28, or CD40L while Tc2 cells express substantial amounts of these ligands that may facilitate their interaction with other immune cells.

View larger version (21K): [in this window] [in a new window]   Figure 3.   Polarized (a) Tc1 and (b) Tc2 CD8+ T cells were generated from v5.2 T cell receptor-transgenic mice by culture with anti-CD3 and anti-CD28 (a) or anti-CD3 and anti-CD28 and PMA and IL-4 (b) for 3 d in vitro and restimulated with PMA and ionomycin and stained for intracellular cytokines. Numbers shown in the FACS quadrants represent the percentage of gated lymphocytes. The corresponding cytokine concentrations in the cell supernatants were as follows: (a) IFN-, 276 ng/ml; IL-4, 0.0 ng/ml; (b) IFN-, 0.4 ng/ml; IL-4, 5.5 ng/ml.

	EFFECTOR FUNCTIONS OF CD8+ T CELL SUBSETS

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CD4⁺ and CD8⁺ T cells share common features but also exhibit marked differences summarized in Table 2. Tc1 and Tc2 CD8⁺ T cells injected into mice induce comparable inflammation (33). Unlike CD4⁺ Th1 and Th2 cells there is, however, no obvious difference in the resultant pathology. In the lung Th1 CD4⁺ T cells induce neutrophilia while Th2 cells induce eosinophilia. CD8⁺ Tc1 and Tc2 cells are equally cytotoxic (34) but only CD4 Th1 cells can induce killing of target cells.

View this table: [in this window] [in a new window]   TABLE 2 COMPARISON OF CD4+ AND CD8+  T CELL SUBSET EFFECTOR FUNCTIONS

	IMMUNE REGULATION BY CD8+ T CELL SUBSETS

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Shortly after IgE was discovered Tada and coworkers showed that Ly2 (CD8)-positive T cells inhibited IgE responses in rats (35). Subsequently, Sedgwick and Holt showed that inhalation of ovalbumin (OVA) led to the activation of CD8⁺ T cells that could inhibit IgE responses after adoptive transfer (38). The cells induced by this route of immunization expressed the form of the T cell receptor (TcR) (39). After exposure to castor bean dust we observed that normal as well as atopic people became sensitized to castor bean proteins (40). In a rat model we showed that the agent responsible was a toxin, ricin, that selectively killed a population of CD8⁺ cells (41, 42) and resulted in the enhancement of the IgE response (43), reduced IFN- production, and increased expression of IL-4 (44), IL-5, and IL-10 (45). Depletion of CD8⁺ T cells 2 wk after immunization enhanced the IgE response and also resulted in increased IL-4 and decreased IFN- production by CD4⁺ T cells (46). Cloned rat OVA-specific CD8⁺ T cells were shown to be MHC class I restricted (47). Unlike the inhibitory effects of virus-specific CD8⁺ T cells on lung eosinophilia described by Hussell and coworkers (48), which appear to be mediated by IFN-, there was no difference in the amount of IFN- produced by cloned CD8⁺ T cells that differed 17-fold in their ability to inhibit IgE (47). Furthermore, in more recent experiments we have shown that both Tc1 and Tc2 OVA-specific CD8⁺ T cells and OVA-specific CD8⁺ T cells from IFN- knockout mice are equally able to inhibit IgE. These cells do not appear to suppress the production of IL-4-producing cells but rather enhance the Th1 response. Thus any antigen getting into the MHC class I pathway at the beginning of an immune response will tend to induce a response with a Th1 bias.

	CD8+ T CELLS IN ASTHMA

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CD8⁺ T cells appear to play different roles in asthma. As described by Hussell and colleagues for viruses (48), OVA-primed Tc1 CD8⁺ T cells inhibit Th2 CD4⁺ T cells and so prevent the development of bronchial hyperresponsiveness (BHR) (20). Depletion of CD8⁺ T cells increases both the early-phase (20) and the late-phase response (49) to OVA. This effect is likely to be related to IFN-. In patients, the presence of CD8⁺ T cells in bronchoalveolar lavage (BAL) after experimental allergen challenge is negatively associated with a late-phase response (50). However, Tc2 CD8⁺ T cells may directly contribute to airway inflammation in asthma. Coyle and colleagues (51) showed that in mice making a strong Th2 response, a concomitant CD8⁺ T cell response to viral infection resulted in an increase in virus-specific CD8⁺ T cells that made IL-5. Subsequent viral infection caused lung eosinophilia. There is evidence for such a phenomenon in allergic patients, where viral infections may contribute to asthma by increasing eosinophil infiltration (52).

	CD8+ T CELLS IN OTHER LUNG DISEASES

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CD8⁺ T Cells in Tuberculosis

CD8⁺ T cells are generally associated with Th1-type immune responses. CD8⁺ T cells play an important role in the generation of protective immunity to Mycobacterium tuberculosis. CD8⁺ T cells have been found in patients with chronic obstructive pulmonary disease (COPD) (53, 54). In mice Tough and coworkers showed that tiny amounts of lipopolysaccharide (LPS) from gram-negative bacteria caused selective activation of CD8⁺ T cells (55). Previous studies in mice, including ₂-microglobulin knockout mice, have suggested an important role for CD8⁺ T cells in host defense to M. tuberculosis (56, 57). Immunization of mice with heat-killed Mycobacterium vaccae induces CD8⁺ T cells specific for M. tuberculosis-infected macrophages (58). In humans CD8⁺ T cells specific for M. tuberculosis have been described (59, 60).

CD8⁺ T Cells and COPD

Relatively little is known about T cells and COPD. O'Shaughnessy and colleagues (53) showed that increased numbers of CD8⁺ T cells were present in the lungs of patients with COPD. A similar finding was reported by Saetta and coworkers (61) and de Jong and colleagues showed that CD8⁺ T cell numbers in the peripheral blood were increased in patients with COPD relative to CD4⁺ T cells. The CD4⁺/CD8⁺ T cell ratio in these patients was negatively correlated with lung function and serum IgE levels (62). However, we still know little about the kinetics of CD8⁺ T cell recruitment, their interaction with CD4⁺ T cells, and their contribution to the pathology of COPD.

	FUTURE QUESTIONS

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Clearly we need to know more about the role of different immune cells, and CD8⁺ T cells in particular, in COPD. Some of these questions may be addressed by monitoring "at risk" patients, but this will be time consuming and expensive. Investigation of large cohorts of patients with COPD may make it possible to identify groups with common factors such as an absence of cigarette smoking. Cigarette smoking exerts different effects on the immune system at different doses, which further compounds the interpretation of results. Animal experiments will allow us to model mechanisms but these will always need to be verified against the human disease.

	Footnotes

Correspondence and requests for reprints should be addressed to Professor David M. Kemeny, Department of Immunology, GKT, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK. E-mail: david.kemeny{at}kcl.ac.uk

Acknowledgments: Supported by research grants from the Wellcome Trust, the Medical Research Council, Bayer Yakuhin, and Glaxo Wellcome.

	References

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