The role of CD1-restricted T cells in infectious diseases (1999)

CD1 molecules constitute an intriguing family of glycoproteins that, despite extensive investigation, remains mysterious1Porcelli S.A. Adv. Immunol. 1995; 59: 1-98Crossref PubMed Scopus (353) Google Scholar. In common with major histocompatibility complex (MHC) class I molecules, they are transmembrane proteins with three extracellular domains and they associate with β2-microglobulin. CD1 proteins are not encoded within the MHC, however, and they lack the polymorphism of MHC class Ia and MHC class II molecules1Porcelli S.A. Adv. Immunol. 1995; 59: 1-98Crossref PubMed Scopus (353) Google Scholar. One of the most interesting immunological findings of the past decade was the discovery that human CD1 proteins present antigens derived from mycobacteria to T cells2Porcelli S.A. Morita C.T. Brenner M.B. Nature. 1992; 360: 593-597Crossref PubMed Scopus (509) Google Scholar. Subsequent studies found that CD1 presents mycolic acid and lipoarabinomannan to T cells, which was a real surprise because immunologists had become comfortable with the notion that T cells only detect peptides in the context of MHC molecules3Beckman E.M. et al.Nature. 1994; 372: 691-694Crossref PubMed Scopus (878) Google Scholar, 4Sieling P.A. et al.Science. 1995; 269: 227-230Crossref PubMed Scopus (672) Google Scholar. These discoveries have opened up an exciting field of study focusing on the cell biology and biochemistry of CD1. The remarkable advances that have been made were recently summarized by Prigozy and Kronenberg5Prigozy T.I. Kronenberg M. Trends Microbiol. 1998; 6: 454-459Abstract Full Text Full Text PDF Scopus (10) Google Scholar. Antigen presentation by CD1 molecules is now recognized as a third pathway, complementing the MHC class I and MHC class II antigen-processing pathways and dramatically extending the breadth of T-cell surveillance to microbial glycolipids1Porcelli S.A. Adv. Immunol. 1995; 59: 1-98Crossref PubMed Scopus (353) Google Scholar. Investigations of CD1 molecules have resulted in several waves of excitement. Although the cell biology and biochemistry of these molecules are becoming increasingly clear, their function in vivo remains nebulous. Three laboratories have generated CD1-deficient mice6Smiley S.T. Kaplan M.H. Grusby M.J. Science. 1997; 275: 977-979Crossref PubMed Scopus (437) Google Scholar, 7Chen Y.H. et al.Immunity. 1997; 6: 459-467Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 8Mendiratta S. et al.Immunity. 1997; 6: 469-477Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar. Although these mice are developmentally normal, they show diminished early production of interleukin 4 (IL-4) in response to T-cell activation in vivo, an effect that has been attributed to the absence of NK1+ T cells, which interact specifically with CD1. Interestingly, the mice still mount normal immunoglobulin E responses, indicating that NK1+ T cells are not required for the development of at least some Th2-type responses. Do CD1-restricted T cells play a role in protective immunity to infection? CD1-restricted T cells can express effector functions associated with protective immunity, including secretion of interferon γ and cytolysis of antigen-treated target cells1Porcelli S.A. Adv. Immunol. 1995; 59: 1-98Crossref PubMed Scopus (353) Google Scholar. In the absence of MHC class-II-restricted CD4+ T cells, it appears that NK1+ CD4+ T cells (which, as noted above, are probably restricted by CD1) can regulate the development of cell-mediated immunity to Toxoplasma gondii infection9Denkers E.Y. et al.J. Exp. Med. 1996; 184: 131-139Crossref Scopus (144) Google Scholar. Following Listeria monocytogenes infection, early IL-4 production by NK1+ T cells has been implicated in the recruitment of monocytes to sites of infection10Flesch I.E. Wandersee A. Kaufmann S.H. J. Immunol. 1997; 159: 7-10Google Scholar. However, there is currently no evidence that CD1-restricted T cells can directly confer protection against infection and no published evidence that CD1-deficient mice are more susceptible to infection. Are CD1-restricted T cells primed by exposure to antigen, and do they expand in vivo and form memory T cells in response to infection? A recent study has investigated whether CD1-restricted T cells can be activated in vivo by exposure to antigen11Lee D.J. et al.J. Exp. Med. 1998; 187: 433-438Crossref Scopus (50) Google Scholar. Using a clever strategy of DNA vaccination, Corr and colleagues have demonstrated that CD1d-restricted cytolytic T-cell responses can be induced in mice11Lee D.J. et al.J. Exp. Med. 1998; 187: 433-438Crossref Scopus (50) Google Scholar. This finding suggests that CD1 complexed with antigen can drive T-cell activation in vivo and, possibly, drive expansion. The recently described methods for quantifying T-cell responses in vivo12Miyahira Y. et al.J. Immunol. Methods. 1995; 181: 45-54Crossref PubMed Scopus (326) Google Scholar, 13Altman J.D. et al.Science. 1996; 274: 94-96Crossref PubMed Scopus (3102) Google Scholar should make it possible to precisely measure CD1-restricted T-cell responses following immunization and infection. Are CD1-restricted T cells only specific for lipids derived from mycobacteria? Although it might seem improbable that CD1 molecules are involved in protection against only one class of pathogen (albeit an important class, given the ravaging infections caused by Mycobacterium tuberculosis and Mycobacterium leprae and the ubiquity of environmental mycobacteria), this kind of narrow utility would not be unprecedented. For example, humans lacking the terminal components of the complement cascade only manifest increased susceptibility to infection by Neisseria gonorrhoeae and Neisseria meningitidis14Petersen B.H. et al.Ann. Intern. Med. 1979; 90: 917-920Crossref PubMed Scopus (187) Google Scholar. However, a recent study indicates that a non-protein antigen derived from Haemophilus influenzae serotype b is also presented to CD1-restricted T cells15Fairhurst R.M. et al.Infect. Immun. 1998; 66: 3523-3526Google Scholar. Although this antigen remains undefined, this study suggests that CD1 molecules play a role in immune defenses against Gram-negative bacteria. We are likely to learn much more in the coming years about the role of CD1-restricted T cells in a range of important infections.