An Alternative Path for Presentation: Group 1 CD1 Jack L. Strominger This information is current as J Immunol 2010; 184:3303-3305; ; of October 4, 2021. doi: 10.4049/jimmunol.1090008 http://www.jimmunol.org/content/184/7/3303

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. An Alternative Path for Antigen Presentation: Group 1 CD1 Proteins Jack L. Strominger 2 2 he epochal discovery of a technique for producing be MHC restricted. An unusual CD4 CD8 double neg- mAbs of defined specificity by Georges Ko¨hler and ative (DN) TCRgd T cell line IDP2 that showed MHC- T Ce´sar Milstein (1) led to many important advances in independent lysis had been described. Among several dozen life sciences and spawned a large industry for production of DN T cell lines that had been generated, equally divided these Abs for research, diagnosis, and therapy. The first mouse among DN TCRab and TCRgd lines, one additional DN anti-human mAb produced by this technique was NA1/34. It TCRab cell line was found that also lysed MOLT4 cells that recognized an Ag called HTA-1 (later called CD1a), expressed do not express any MHC proteins (5). However, MOLT4 on human and some B lymphoma cell lines (2). was well known to express all three CD1a, CD1b, and CD1c Downloaded from Because this and related proteins were among the first human molecules. mAb blocking experiments established that the lymphocyte markers identified with the newly invented mAb TCRs were each involved in the lysis phenomenon. More- technology, they entered the immunological lexicon as the over, the unusual DN TCRgd cell line was specific for CD1a, first cluster of differentiation molecules or “CD1.” Genomic whereas the DN TCRab cell line was specific for CD1c. 1 1 and sequence analysis established that this and four Later, CD4 (and some CD8 ) T cells that recognize CD1 paralogues on human 1 encoded closely related proteins were found, and the DN characteristic that led to the http://www.jimmunol.org/ proteins called CD1a, CD1b, CD1c, CD1d, and CD1e, discovery diminished in importance. which were distantly related to the H chains of human MHC The door was open. In two subsequent papers, it was class I proteins HLA-A, -B, and -C encoded on chromosome established first that a microbial Ag could be presented by 6 (3, 4). Moreover, these proteins were associated with b2- a CD1 molecule (6) and then that the foreign Ag was a lipid microglobulin, which is encoded on chromosome 15 and also (7). PBLs were stimulated with an extract of Mycobacterium found in HLA proteins. On the basis of sequence compar- tuberculosis, and a cell line, DN1, was obtained that pro- isons, the molecules could be divided into group 1, com- liferated to the extract and to that of M. leprae, but not to prising CD1a, CD1b, CD1c, and CD1e, and group 2, several other organisms. The Ag extract was presented by containing only CD1d. Surprisingly, however, the mouse CD1-expressing and was not MHC restricted. by guest on October 4, 2021 contains no group 1 CD1 but has two group 2 CD1d Moreover, the response was blocked by CD1b mAb, but not genes, whereas the rat contains only one CD1d, and other by CD1a or CD1c mAb, nor by pan-MHC class I or MHC rodents and mammals may contain 8–12 group 1 CD1 genes. class II mAbs. Further, only CD1b transfectants, not CD1a or Why had these MHC class I-like genes with limited poly- CD1c transfectants, could present Ag in the extracts. Thus, in morphism evolved separately from their longer known poly- three short papers, novel T cell lines specific for CD1a, morphic cousins? CD1b, or CD1c had been described. The Ag recognized by Their function or functions were also obscure, but once the DN1 clone was protease resistant and extractable into again, simple but logical direct questions, followed by organic solvents. Reverse phase HPLC was used to show that experiments, led to the answer. If the function of the poly- the active component coeluted with mycolic acid, a lipid that morphic MHC class I proteins was to present peptides with forms the outer coat of mycobacteria. A new class of Ag- different sequences to the immune system, was it possible that presenting proteins had been found for lipid Ags. the CD1 proteins were also Ag-presenting molecules? Were The floodgates were open, and a profusion of papers have there circulating T cells that would recognize CD1 molecules? appeared in the past 15 y (reviewed in Refs. 8–10). Important The answers were provided in three important papers (5–7), advances were made in four specific areas: identification of the the first of which is reprinted here in Pillars of Immunology. lipids recognized; crystallization of several CD1 proteins, re- Because CD1 proteins are distinct in sequence and structure vealing the manner in which lipid moieties lead to binding of from MHC proteins, T cells that recognize CD1 should not these Ags; the different trafficking pathways for CD1a, CD1b, and CD1c; and, most importantly, in vivo studies of the possible role or roles of these CD1 proteins in the patho- Department of Stem Cell and Regenerative Biology and Department of Molecular genesis of and/or protection from infection. The additional and Cellular Biology, Harvard University, Cambridge, MA 02138 MHC-like proteins present on human , group This work was supported by National Institutes of Health Research Grant AI049524. 2 CD1d and MR1, are beyond the scope of this commentary. Address correspondence and reprint requests to Dr. Jack L. Strominger, Department of Molecular and Cell Biology, Harvard University, Fairchild 407, 7 Divinity Avenue, A large number of lipids that bind to the three CD1 proteins Cambridge, MA 02138. E-mail address: [email protected] have been identified. Although these molecules have been Abbreviation used in this paper: DN, double negative. referred to as “lipid Ags,” this label seems a slight misnomer Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 because the lipid moieties themselves embed these molecules www.jimmunol.org/cgi/doi/10.4049/jimmunol.1090008 3304 PILLARS OF IMMUNOLOGY to the CD1 proteins, whereas hydrophilic head groups of the and/or protection from infection? Can the information gained Ags are recognized by T cells. The lipids are mainly glyco- be used to develop vaccines against important pathogens, lipids and lipopeptides, and only in rare cases, like mycolic particularly M. tuberculosis, which causes worldwide mor- acid, is the lipid itself recognized. “Lipid-linked Ags” would bidity and mortality nearly equal to that of HIV and has been be a more precise term. Many of the lipids recognized come a plague at least since the time of the pharaohs? Expansion of from important human pathogens such as M. tuberculosis, M. CD1-restricted T cells and secretion of IFN-g has been clearly leprae, Leishmania, and Borrelia burgdorferi (the causative demonstrated in infections, particularly those with M. tuber- agent of Lyme disease). In mycobacteria, for example, up to culosis (19, 20). At this point, though, data indicating that 40% of the cell wall may be composed of lipids. these T cell responses are protective are still lacking. Micro- CD1a and CD1b were crystallized. The resulting structures organisms also have been reported to be able to either upre- demonstrated different ways that lipids are bound to these gulate or downregulate expression of CD1 proteins on proteins. Both use hydrophobic pockets called A9 and F9 to monocytes (10, 21, 22) (K. Yakimchuk, C. Roura-Mir, T.-Y. bind lipids (related in position and function to the A and F Cheng, S. R. Granter, R. Budd, A. Steere, V. Pena-Cruz, and pockets in MHC class I proteins that bind amino acid side D. B. Moody, submitted for publication). Because the mouse chains). CD1b also has a C9 pocket that mainly provides lacks group 1 CD1 proteins, a mouse model has not been a portal to the exterior and a T9 (for tunnel) pocket, features available. However, the recent construction of a mouse that may allow accommodation of very large lipids (11–13). A transgenic for human CD1a, CD1b, and CD1c may make it computational model of the CD1c structure has recently possible to design an experiment in which protection can be appeared. It is distinguished from its close cousins by the size demonstrated (23). Similarly few data on vaccination with Downloaded from of the F9 pocket; the absence of pockets C9 and T9; and the lipid-linked Ags are available (24–27). Of particular interest is possible presence of a new portal, D9 (14). a recent study of cattle immunized with mycobacterial glucose The distinctive trafficking pathways of the group 1 CD1 monomycolate (27). Cattle express CD1a, CD1b, and CD1c, proteins that lead to loading of the lipid-linked Ags are most but no CD1d. In this species, infections with M. bovis and interesting (10). After biosynthesis in the endoplasmic re- M. avium subsp. paratuberculosis cause important economic ticulum and Golgi, where binding of self-lipids occurs, these problems. Strong T cell responses to immunization were http://www.jimmunol.org/ molecules first travel to the cell surface. Direct loading of generated. Much work in this area remains to be done, but the lipids may occur at the surface, but in addition these proteins, basic scientific foundations have been laid. although they resemble MHC class I proteins structurally, traffic through the endosomal compartments, where loading and/or exchange with exogenous lipid-linked Ags occurs, in Disclosures a manner similar to the MHC class II proteins. The three The author has no financial conflicts of interest. group 1 CD1 proteins have distinct trafficking pathways. CD1a, which has only a short cytoplasmic tail, remains largely by guest on October 4, 2021 at the surface and follows the shallow endosomal recycling References 1. Ko¨hler, G., and C. Milstein. 1975. Continuous cultures of fused cells secreting pathway of MHC class I. By contrast, CD1b and CD1c have antibody of predefined specificity. Nature 256: 495–497. longer tails encoding endosomal sorting motifs that use AP2 2. McMichael, A. J., J. R. Pilch, G. Galfre´, D. Y. Mason, J. W. 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