Shapes of MHC Restriction Review

Immunity, Vol. 10, 1±7, January, 1999, Copyright 1999 by Cell Press Shapes of MHC Restriction Review David N. Garboczi*³ and William E. Biddison²³ structures of a TCR b subunit and a Va domain con- *Structural Biology Section firmed predictions that the TCR V and C domains are National Institute of Allergy and Infectious Diseases very similar to the corresponding structures observed National Institutes of Health in antibody molecules (Bentley and Mariuzza, 1996). Rockville, Maryland 20852±1727 Each of the three CDR loops protrude from the same ² Molecular Immunology Section face of the molecule. A fourth loop, termed HV4, is also Neuroimmunology Branch present. The exception to these similarities has been National Institute of Neurological Disorders the C domain of the a chain that has a noncanonical and Stroke fold (Garcia et al., 1996; Ding et al., 1998). Structural National Institutes of Health studies of entire abTCR molecules were slowed by the Bethesda, Maryland 20892 the inability to produce sufficient amounts of TCR protein to analyze, but in the last three years, several X-ray structures of human and murine abTCRs complexed The defining component of antigen-specific recognition with peptides bound to MHC class I molecules have by T lymphocytes with ab T cell receptors (TCRs) is been determined. Two different human abTCRs were MHC restriction. The concept of MHC restriction was identified in CD81 cytotoxic T cell clones (A6 and B7) derived from experiments which showed that virus-spe- specific for the Tax 11±19 peptide (LLFGYPVYV) of hu- cific effector T cells could only lyse virus-infected target man T cell lymphotrophic virus type-1 (HTLV-I) pre- cells that were of the same MHC haplotype as the ef- sented by HLA-A2 and were isolated from the peripheral fector T cells (Zinkernagel and Doherty, 1974). Two mod- blood of HTLV-I-infected patients (Utz et al., 1996). The els were proposed to explain the mechanism by which A6 and B7 a and b chains were individually expressed an uncharacterized TCR could be specific for both the in bacteria, then refolded and bound to soluble forms foreign antigen (e.g., virus) and self-MHC molecules: (1) of HLA-A2 complexed with the Tax peptide and crystal- ªaltered self,º in which a given MHC molecule was al- lized (Garboczi et al., 1996a, 1996b; Ding et al., 1998). A murine abTCR was obtained from a CD81 cytotoxic tered in an undefined, specific way that could be recog- T cell clone (2C) that was derived from alloimmunization nized by a single TCR; and (2) ªdual recognition,º in of H-2b mice with H-2d cells and was initially shown to which two distinct receptors independently recognized be specific for H-2Ld (Kranz et al., 1984). The 2C TCR the foreign antigen and the self-MHC molecule. Two was subsequently shown to be able to recognize the subsequent discoveries favored the altered self hypoth- self-peptide dEV8 (EQYKFYSV) derived from a mito- esis. First, MHC molecules were found to be peptide- chondrial protein presented by H-2Kb (Tallquist et al., binding molecules; each MHC molecule specifically 1996). The a and b chains of 2C were expressed together binds a restricted set of peptides derived from foreign in Drosophila melanogaster cells and were crystallized and self-proteins and presents them on cell surfaces to T alone and complexed with soluble dEV8/H-2Kb com- cells (Townsend et al., 1985; Falk et al., 1991). Moreover, plexes (Garcia et al., 1996, 1998). Another murine abTCR structural studies of peptide/MHC complexes showed was obtained by a different group from a CD81 cytotoxic that the surface of each complex was composed of T cell clone (N15) that was derived from mice immunized MHC elements and amino acid side chains of the bound with vesicular stomatitis virus (VSV) and shown to recog- peptide that protruded upward out of the MHC molecule nize the VSV8 peptide (RGYVYQGL) presented by H-2Kb binding site where they could be contacted by a TCR (Shibata et al., 1992). The a and b chains of N15 were (Fremont et al., 1992; Madden et al., 1993; Stern et al., expressed together in Chinese hamster ovary cells (Liu 1994). Second, the TCR responsible for specificity for et al., 1996) and crystallized with and without the soluble both the foreign antigen and MHC was shown to be a VSV8/H-2Kb complexes. Although the N15 TCR structure single cell surface heterodimeric protein composed of is determined to 2.8 AÊ resolution (Wang et al., 1998), the a and b chains (Hedrick et al., 1984; Yanagi et al., 1984; report of the N15/H-2Kb structure is of low resolution Yague et al., 1985; Dembic et al., 1986). The question (Teng et al., 1998). posed by these discoveries was this: how does a single abTCR embody specificity for both foreign (and self-) Orientation of abTCRs on the peptides plus the MHC? The most direct way to answer Peptide/MHC Complex this question was to determine the protein structure of Each of the Tax peptide±specific TCRs (A6 and B7) and the TCR bound to a peptide/MHC complex. the 2C TCR bind to the peptide/MHC complexes in a The abTCR is similar to an antibody Fab fragment in diagonal orientation. A similar mode of binding was ob- that it consists of two disulfide-linked chains, a and b, served in the N15 TCR/H-2Kb complex. The TCRs bind each containing a variable (V) and constant (C) domain. diagonally between the high points on the a1a2 helices Each variable domain has three complementarity-deter- of the MHC molecule (Figure 1). It appears that this mining regions (CDR1, CDR2, CDR3), with the highest alignment of TCR and MHC is necessary in order for the sequence diversity occuring in the CDR3 region (re- TCR to interact with the relatively small area of peptide viewed in Davis et al., 1998). The first three-dimensional surface that is not buried in the MHC molecule (Garboczi et al., 1996b; Ding et al., 1998). Bound to the MHC molecule in this way, the CDR1 loop of the a chain is posi- ³ E-mail: [email protected] and [email protected]. tioned over the N-terminal end of the peptide, and the Immunity 2 central peptide side chain that protrudes out of the MHC binding site. This feature of TCR recognition suggests that peptide side chains that are protruding from the middle of the MHC groove will be most important for TCR recognition. Second, it places the germline-encoded CDR2 loops over each of the MHC a helices, which provides a docking mechanism that will not be disrupted by the somatic diversification mechanisms that contrib- ute to CDR3 diversity. In each of the three TCR/peptide/ MHC complexes (A6, B7, and 2C), multiple atomic con- tacts exist between amino acid residues in the CDR2a or CDR2b loops and conserved amino acid residues on the a1 and a2 helices of the MHC. Since the CDR2a and CDR2b segments from different Va and Vb genes have conserved amino acid motifs (Arden, 1998), it is possible that conserved CDR2 motifs provide a com- monality which permits different V region CDR2s to bind to any class I molecule that displays its own conserved residues on the a1 and a2 helices. Such a conserved docking structure could provide an explanation for the difficulty in inducing MHC-restricted antibodies. While antibody CDR3 loops could bind to the peptide side chains that point up out of the MHC molecule, antibodies do not have the conserved sequence motifs of the CDR2 Figure 1. Side View of the Four Known TCR/MHC Orientations loops of TCR V segments and may thus have difficulty Ribbon depiction of the human A6 and B7 and the mouse 2C and docking onto the MHC molecule. N15 TCRVaVb regions oriented on their respective MHC complexes. To date, a structure has not been reported of the The VaVb domains are shown in red (Va) and in green (Vb). In blue are the helices (front, a2; back, a1) of the MHC molecules. In gray complex of a TCR and a peptide/MHC class II molecule, is the b sheet forming the floor of the MHC peptide-binding site. This so it is not yet known if this diagonal mode of TCR figure was made by superimposing (program LSQMAN [Kleywegt, interaction with peptide/MHC class I molecules will be 1996]) each MHC a1a2 domain on to the a1a2 domain of HLA- applicable to class II interactions. However, studies on A2 using coordinates deposited at the Protein Data Bank (PDB) class II±restricted TCR recognition using TCR mutagen- (accession numbers 1ao7, 1bd2, and 2ckb) and from J.-H. Wang esis (Engel and Hedrick, 1988; Katayama et al., 1995) (Teng et al., 1998) and by depicting the orientations with the program MOLSCRIPT (Kraulis, 1991). Not shown are the constant domains and TCR selection by variant peptide immunization (Jor- of the TCR and the a3 and b2m domains of the MHC molecule. gensen et al., 1992; Sant'Angelo et al., 1996) all provide indirect evidence that the use of such a diagonal binding mode will also be true for class II±restricted TCR recog- CDR1 loop of the b chain is over the C-terminal end of nition. the peptide. The CDR2 loop of the a chain is positioned over the MHC a2 helix, and the CDR2 of the b chain lies over the MHC a1 helix. The CDR3 loops of both a and TCR Interactions with Peptides b chains combine to form a central pocket that can bind In theory, the TCR could interact with any part of an a peptide residue that extends from the surface of the MHC-bound peptide that is not buried in the MHC mole- MHC molecule.

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