PERSPECTIVE
Dendritic-cell Regulation of Lung Immunity

Marc Dupuis and Donald M. McDonald

Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco; and CHIRON Vaccines, Emeryville, California

	Article

Top Article References

Dendritic cells (DCs) play a central role in initiating protective T-cell immune responses in the respiratory tract. DCs, with long, intertwined cytoplasmic processes at the base of the airway epithelium, form a network ideally positioned to sample inhaled antigens for subsequent presentation to T cells (1). The molecular signals expressed by DCs that lead to T-cell responses are now being unraveled. The recent report by Masten and colleagues in the American Journal of Respiratory Cell and Molecular Biology (2) takes a step in this direction by elucidating the properties of costimulatory molecules on the surface of DCs in the lung. The study provides additional evidence that a unique collection of stimulatory surface proteins mediates the mitogenic effect of DCs on naive T cells.

DCs were originally identified by their capacity to initiate T-cell-dependent immune responses. These responses involve three steps (3). First, DCs in tissues take up and process antigens. Second, DCs migrate to lymphoid organs, probably via afferent lymphatics, and in the process lose their antigen-processing capacity. Third, once in lymphoid tissue, DCs present antigen and stimulate the clonal development of antigen-specific T cells. The exceptional mitogenic capacity of DCs can be demonstrated in vitro by measuring lymphocyte proliferation in a mixed lymphocyte reaction (3). The ability of antigen-exposed DCs to activate T cells and initiate protective immunity has also been shown in vivo (4).

Presentation of antigen by DCs is not by itself sufficient to activate T cells. Antigens presented in the context of major histocompatibility complex (MHC) molecules initiate T-cell-dependent immune responses in conjunction with surface proteins on DCs. In the absence of costimulatory signals mediated by such surface proteins, T cells become unresponsive or fail to proliferate. Several ligand/ receptor systems are essential for immunogenicity, including lymphocyte function-associated antigen-1 (LFA-1)/ intercellular adhesion molecule-1 (ICAM-1), ICAM-1/ LFA-1, clonal designator-2 (CD2)/LFA-3, CD40/CD40L, and the B7/CD28-CTLA-4 pathway (5). Expression of ICAM-1 and CD40L may contribute to the recruitment of several immune cells, including CD4⁺ and CD8⁺ T cells as well as B cells. The B7 molecules, comprising B7-1 (CD80) and B7-2 (CD86), interact with CD28 and the inducible homologue CTLA-4. Interactions between CD80 and CD86 on the surface of DCs with CD28 and CTLA-4 on the surface of T cells regulate T-cell activation and cytokine production (6).

DCs activate both cytotoxic T cells (CD8⁺) and helper T cells (CD4⁺). The latter can be divided into two subsets: Type 1 helper T (Th1) cells, which produce interferon- (IFN-) and interleukin-2 (IL-2), and Type 2 helper T (Th2) cells, which produce IL-4, IL-5, IL-10, and IL-13 (7). Th1 and Th2 cells were originally identified in mice. Similar subsets exist in humans, but the distinctions are less sharp than in mice, and some T-helper cells have features of both phenotypes. Th1 cells and Th2 cells appear to have different functions. Th1 cells mediate delayed hypersensitivity, activate macrophages, and in mice switch antibody production from IgM to IgG2a. In contrast, Th2 cells promote a switch from IgM to IgG1 and IgE antibodies. Antigen-mediated crosslinking of IgE antibodies bound to receptors on mast cells triggers the allergic cascade through the release of vasoactive mediators, chemotactic factors, and cytokines. Because of the prominent role of IgE in the allergic cascade, factors that control the IgE response are an important focus in the development of therapeutic strategies for allergic disease.

Certain cytokines exert a potent effect on T-cell differentiation. IL-12 activates a transcription factor (Stat4) that induces IFN- production and differentiation into the Th1 phenotype. Spleen cells from mice that lack the Stat4 gene do not proliferate in response to IL-12, but tend to develop into Th2 cells (8). IL-4 activates another transcription factor (Stat6), which promotes Th2-cell differentiation. B cells from mice deficient in the Stat6 gene fail to upregulate MHC Class II molecules in response to IL-4, and have an impaired immunoglobulin isotype switching to IgE (9). Although there is convincing evidence that IgE production is controlled by IL-4 from Th2 cells, the cells and molecular signals that control IL-4 secretion are at an early stage of characterization.

The balance between Th1 and Th2 responses is influenced by ligand/receptor interactions. Experiments with selective agonists and blocking antibodies demonstrate that, through CD80 and CD86 on DCs, the B7/CD28- CTLA-4 signaling pathway dictates the profile of cytokines that control the differentiation of Th1 and Th2 cells (10). In a rat model of experimental allergic encephalomyelitis, blockade of the B7/CD28-CTLA-4 pathway inhibits the Th1 response, but does not affect Th2 responses (11). In sharp contrast, blockade of the B7/CD28-CTLA-4 pathway in a mouse model of allergen-induced airway hyperresponsiveness suppresses Th2 responses (12). The basis of these differences is not known, and it is difficult to make a clear correlation between B7 molecules and the generation of Th1 or Th2 responses. However, the discrepancies may be due to differences in levels of B7 expression in the two species (Figure 1).

View larger version (9K): [in this window] [in a new window]   Figure 1.   Model of T-cell differentiation induced by CD80 and CD86 expressed on the surface of dendritic cells. Antigen is presented in the context of the MHC on the surface of DCs. Antigen recognition by the T-cell receptor (TCR) triggers T-cell differentiation into Th1 or Th2 cells, depending on whether CD80 and/or CD86 is the ligand.

The mechanism by which surface proteins on lung DCs regulate T-cell differentiation is the key to understanding immunologic responses of the respiratory tract. Masten and colleagues (2) addressed the mechanism by analyzing the role of DC surface molecules in the activation of naive allogeneic T cells. Using mouse-lung DCs obtained through a multistep purification procedure in combination with cell sorting by flow cytometry, Masten and colleagues found, as expected, that DCs had a potent mitogenic effect on T cells as measured by lymphocyte proliferation. This mitogenic effect of DCs was increased by the presence of lung interstitial (not alveolar) macrophages, and was dependent on interactions with multiple surface molecules, including ICAM-1 and CD40L. Remarkably, anti-CD80 antibodies inhibited lymphocyte proliferation, whereas anti-CD86 antibodies did not significantly change the mitogenic effect unless anti-CD80 antibodies were also present. Thus, the effect of CD80 dominated the effect of CD86 on T-cell proliferation.

Because CD80 favors Th1-cell differentiation in some models (10, 11), it is tempting to speculate that the normal lung provides an environment that favors the development of Th1 responses. However, recent results suggest that the relationship between the B7/CD28-CTLA-4 pathway and the generation of Th1 and Th2 cells may be different in the airways: blockade of the B7/CD28-CTLA-4 pathway results in a decrease of antigen-induced allergic Th2 responses (12). Further studies are required to resolve the important issue of the role of costimulatory molecules in the establishment of Th1 or Th2 responses of the airways. It will be essential to directly study the consequences of the engagement of CD80 and CD86 expressed at the surfaces of lung dendritic cells on the development of T-cell responses. Because T-cell responses are affected by the relative amounts of costimulatory molecules, monitoring changes in B7 expression during DC maturation in vitro and in comparative studies of normal and allergic responses in situ may yield useful information.

In humans, it is not clear how Th1 and Th2 responses affect each other, and multiple immune responses may coexist. However, immune responses dominated by cytokines of the Th2 phenotype have been linked to the pathogenesis of allergic disease. For example, a recent study of children in Japan showed that serum IgE concentrations were inversely related to delayed cutaneous hypersensitivity to tuberculin (13). Children with positive tuberculin responses had serum cytokines suggestive of a Th1 profile, whereas children with negative tuberculin responses had Th2 serum cytokine profiles. The latter group was more prone to asthma.

The observation that an imbalance of Th1 and Th2 responses may trigger immunologic disorders has prompted the search for strategies to re-establish the balance between the two types of responses. Historically, cytokines have received much attention in this context because of their potent effects on T-cell differentiation. However, direct administration of cytokines has proven to have limited usefulness, in part because of their short half-life in vivo. Yet several factors other than cytokines contribute to T-cell differentiation in vivo, including genetic background; conditions that modulate surface proteins; and dose, route of administration, and formulation of the antigen (with or without adjuvant). In the context of clinical intervention for preventing or treating asthma, it remains to be established whether populations of Th2 cells can be changed into more favorable Th1 cells. In this regard, the effectiveness of an agent that reverses immune Th1 or Th2 responses may depend on the timing of the treatment in relation to the development of these immune responses. Importantly, because Th1 cells have been linked to autoimmune disease (10, 11), manipulation of the Th1/Th2 balance has potential risks. Clearly, a more complete understanding of these complex events is needed before reagents that target costimulatory surface proteins on DCs can be considered in the routine treatment of allergic disease.

	Footnotes

Address correspondence to: Marc Dupuis, Ph.D., Department of Anatomy, Box 0452, 513 Parnassus Avenue, University of California, San Francisco, CA 94143-0452. E-mail: Dupuis{at}itsa.ucsf.edu

.

Acknowledgments: Supported in part by National Heart, Lung and Blood Institute Program Project Grant HL-24136.

	References

Top Article References

1. Schon-Hegard, M. A., J. Oliver, P. G. McMenamin, and P. G. Holt. 1991. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J. Exp. Med. 173: 1345-1356 [Abstract/Free Full Text].

2. Masten, B. J., J. L. Yates, A. M. Pollard, Koga, and M. F. Lipscomb. 1997. Characterization of accessory molecules in murine lung dendritic cell function: roles for CD80, CD86, CD54, and CD40L. Am. J. Respir. Cell Mol. Biol. 16: 335-342 [Abstract].

3. Steinman, R. M.. 1991. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9: 271-296 [Medline].

4. Macatonia, S. E., P. M. Taylor, S. C. Knight, and B. A. Askonas. 1989. Primary stimulation by dendritic cells induces antiviral proliferative and cytotoxic T cell responses in vivo. J. Exp. Med. 169: 1255-1264 [Abstract/Free Full Text].

5. Collins, T. L., P. D. Kassner, B. E. Bierer, and S. J. Burakoff. 1994. Adhesion receptors in lymphocyte activation. Curr. Opin. Immunol. 6: 385-393 [Medline].

6. Lenschow, D. J., T. L. Walunas, and J. A. Bluestone. 1996. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14: 233-258 [Medline].

7. Romagnani, S.. 1995. Biology of human Th1 and Th2 cells. J. Clin. Immunol. 15: 121-126 [Medline].

8. Kaplan, M. H., Y. L. Sun, T. Hoey, and M. J. Grusby. 1996. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382: 174-177 [Medline].

9. Shimoda, K., J. van Deursen, M. Y. Sangster, S. R. Sarawar, R. T. Carson, R. A. Tripp, C. Chu, F. W. Quelle, T. Nosaka, D. A. A. Vinali, P. C. Doherty, G. Grosveld, W. E. Paul, and J. N. Ihle. 1996. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380: 630-633 [Medline].

10. Kuchroo, V. K., M. P. Das, J. A. Brown, A. M. Ranger, S. S. Zamvil, R. A. Sobel, H. L. Weiner, N. Nabavi, and L. H. Glimcher. 1995. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 development pathways: application to autoimmune disease therapy. Cell 80: 707-718 [Medline].

11. Khoury, S. J., L. Gallon, R. R. Verburg, A. Chandraker, R. Peach, P. S. Linsley, L. A. Turka, W. W. Hancock, and M. H. Sayegh. 1996. Ex vivo treatment of antigen-presenting cells with CTLA4Ig and encephalitogenic peptide prevents experimental autoimmune encephalomyelitis in the Lewis rat. J. Immunol. 157: 3700-3755 [Abstract].

12. Keane-Myers, A., W. C. Gause, P. S. Linsley, S.-J. Chen, and M. Wills-Karp. 1997. B7-CD28/CTLA-4 costimulatory pathways are required for the development of the T helper cell 2-mediated allergic airway responses to inhaled antigens. J. Immunol. 158: 2042-2049 [Abstract].

13. Shirakawa, T., T. Enomoto, S. Shimazu, and J. M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorder. Science 275: 77-79 [Abstract/Free Full Text].