CD 1restricted antigens

Among the most unique features of the CD1 family members is the ability of certain CD1 molecules to present nonpeptide antigens to T cells. At least three classes of antigens have been shown to be presented by CD1 molecules, i.e. a lipid moiety, a lipoglycan and peptide antigens were recognized by CD1-restricted T cells.

In 1994, a group of scientists at Harvard University described the first CD 1-restricted antigen as a protease-resistant moiety that copurified with the lipid fraction of the mycobacterial extract. Biochemical analysis of this antigen showed that it is a member of the mycobacterial family of mycolic acids (Figure 3). The fact that mycolic acid is found in the cell wall of several bacterial species such as Nocardia and Corynebacterium spp. suggests that CD1 molecules may present antigens derived from bacterial pathogens other than mycobacteria. A year later, these findings were extended by describing two Mycobacterium leprae-specific CD lb-restricted human T cell lines that recognize lipoarabinomannan (LAM), a glycolipid from the mycobacterial cell wall, and do not cross-react with mycolic acid. This molecule belongs to the lipoglycan family and is com-

Figure 3 Mycolic acids are high molecular weight a-branched, 0-hydroxy fatty acids that are components of the cell wall of all mycobacteria. All known mycolic acids have the basic structure R2CH(0H)CHR1C00H where R1 is a C-20-C-24 linear alkane and R2 is a more complex structure of 30-90 carbon atoms that may contain various numbers of carbon-carbon double bonds and/or cyclosporane rings, methyl branches and oxygen function groups such as C = 0, CH30CH = C00H. Three principal categories of mycolic acid are known, i.e. corynomycolic acids (C-2& C-40), nocardomycolic acid (C-40-C-60) and mycobacterial mycolic acids (C-60-C-90), produced by strains of Corynebacterium, Nocardia and Mycobacterium, respectively.

Figure 3 Mycolic acids are high molecular weight a-branched, 0-hydroxy fatty acids that are components of the cell wall of all mycobacteria. All known mycolic acids have the basic structure R2CH(0H)CHR1C00H where R1 is a C-20-C-24 linear alkane and R2 is a more complex structure of 30-90 carbon atoms that may contain various numbers of carbon-carbon double bonds and/or cyclosporane rings, methyl branches and oxygen function groups such as C = 0, CH30CH = C00H. Three principal categories of mycolic acid are known, i.e. corynomycolic acids (C-2& C-40), nocardomycolic acid (C-40-C-60) and mycobacterial mycolic acids (C-60-C-90), produced by strains of Corynebacterium, Nocardia and Mycobacterium, respectively.

NH2XXXX1XX4XX7XXXCOOH F I W W L M

Figure 4 Mouse CD1 binds peptides with a sequence motif comprising aromatic, bulky and hydrophobic amino acids with an overhanging NHrterminus. The majority of these long peptides include aromatic residues at positions 1 and 7 and an aliphatic residue in position 4. F, Phenylalanine; W, tryptophan; L, leucine; I, isoleucine; M, methionine; X, any amino acid.

posed of a hydrophobic lipid-containing phosphatidyl inositol group attached to a large and complex hydrophilic heteropolysaccharide. Further studies using chemically modified LAM and related compounds showed that both carbohydrate and lipid components of the antigen were required for presentation and/or T cell recognition. In addition, these two T cell lines differed in their ability to recognize LAM purified from different species of mycobacteria, suggesting a significant level of specificity in CD1-restricted T cell responses. This distinct recognition may arise from subtle variations in the lipid and carbohydrate moieties of LAM.

The previous examples suggest that CD1 proteins could have evolved to present nonpeptide lipid antigens to T cells. However, using random peptide phage displayed libraries, mouse CD1 was shown to bind peptides with a sequence motif comprising aromatic, bulky and hydrophobic amino acids with an overhanging NH2-terminus (Figure 4). The study identified several dozen peptides which appear to be of immunological relevance as they can elicit specific CD 1-restricted CD8+ cytotoxic T lymphocytes (CTLs). The length of these peptide antigens was not critical; however, the majority of these peptides include aromatic residues at positions \ and 7 and an aliphatic residue in position 4. The characteristics of the mouse CD 1-peptide interactions are similar to the interactions of MHC class II molecules with its ligands. For example, in common with class II ligands, mouse CD1 appears to prefer long peptides with hydrophobic and bulky amino acids at certain positions. In addition, the affinity of interaction of these peptides is similar to that of naturally processed peptides copurified with class II molcules.

Although mouse CD1 has been shown to bind peptides, it is not known if mycolic acid and the other lipoglycans directly bind to CDlb. In addition, it is not yet known whether CDlb presents one or more members of the mycolic acid families to T cells as a processed or intact molecule, or as part of a modified epitope.

Interestingly, the amino acid sequence of all known CD1 molecules from various mammalian species, as well as another MHC-unlinked molecule, neonatal Fc-receptor (FcRn), share a proline at position 162 in the a2 helix. Recent crystallographic studies of FcRn showed that Proline 162 induces a kink that closes the peptide-binding groove, thus preventing peptide binding. If this kink is found in CD1 molecules, then it is possible that the interaction between CD1 molecules and their ligands is different from that known for conventional MHC class I molecules. Also, it may resemble that of MHC class II-superantigen association. In addition, the full range of antigens presented by the CD1 molecules is not yet known and the natural ligands remain to be defined. However, studies from several laboratories support the hypothesis that CD1 molecules contain a hydrophobic pocket between the al and a2 domains capable of accommodating lipids, glycol ipids or

Table 2 Comparison between CD1, MHC class I and MHC class II molecules
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