ReviewStructural basis of T cell recognition of peptides bound to MHC molecules
Introduction
Adaptive immunity provides the basis of recognition of foreign pathogens and tumors (Reinherz et al., 1983, Marrack and Kappler, 1986, Clevers et al., 1988, Davis and Bjorkman, 1988, Ashwell and Klausner, 1990). This specific immunity is dependent on the recognition function of the αβ T cell receptor (TCR) on T lymphocytes which detects a protein fragment (i.e. peptide) of a self-protein or cell-associated pathogen (derived from either viral, bacterial, fungal, parasitic or tumor cell origin) bound to an MHC molecule. Physical binding of the peptide–MHC (pMHC) to a TCR initiates a series of signal transduction events involving the αβ TCR heterodimeric structure in conjunction with the monomorphic CD3 signaling components which collectively comprise the TCR (Alarcon et al., 1988, Reth, 1989, Koning et al., 1990, de la Hera et al., 1991, Irving and Weiss, 1991, Manolios et al., 1991, Letourneur and Klausner, 1992, Punt et al., 1994, Ghendler et al., 1998, Sun et al., 2001). This TCR recognition/signaling process is also dependent upon the concomitant recognition of the same pMHC by an MHC class-restricted co-receptor (Kruisbeek et al., 1985, Marrack and Kappler, 1986, Janeway, 1992, Wang and Reinherz, 2000). CD8 and CD4 serve as co-receptors for pMHCI and pMHCII recognition, respectively.
During the last several years, structures of these αβ TCR heterodimers or domain fragments thereof, alone or in complex with peptide-bound MHC molecules have been determined (see below). This includes the two most recent structures of TCRs from αβ helper T cells that recognize class II MHC molecules (Reinherz et al., 1999, Hennecke et al., 2000). Furthermore, the structural basis of CD8αα–pMHCI (Gao et al., 1997, Kern et al., 1998) and CD4–pMHCII (Wang et al., 2001) interactions have been defined and the bidentate nature of TCR and co-receptor binding to pMHC discerned. This review will focus on the nature of TCR and co-receptor interaction with pMHC, with particular emphasis on the CD4-derived helper T cell system. Implications of these findings for thymic selection, immune recognition and alloreactivity will be discussed.
Section snippets
A common TCR–MHC docking mode
There are more than half a dozen crystal structures of αβ TCRs complexed to their cognate antigenic pMHC ligands. Those include both class I (Garboczi et al., 1996, Garcia et al., 1996, Ding et al., 1998, Garcia et al., 1998, Teng et al., 1998) and class II complexes (Reinherz et al., 1999, Hennecke et al., 2000). These works in general support a common docking mode of TCRs towards the peptide–MHC complex (Davis and Bjorkman, 1988, Jorgensen et al., 1992, Sant’Angelo et al., 1996, Chang et al.,
pMHC-dependent binding topology
There does not appear to be significant structural differences between class II versus class I specific TCRs themselves. Virtually the entire V module of the D10 and B7 TCR can be superimposed (Reinherz et al., 1999). The conserved TCR docking topology seems to be pMHC-dependent. Garboczi et al. (Garboczi et al., 1996) first realized that there are two high “peaks” near the N-termini of the two α-helical regions that form the walls of the peptide-binding groove. It was subsequently observed (
Recognition of antigenic peptide
While the antigenic peptide is usually much longer in pMHCII (13–25 residues) than in pMHCI (8–10 residues), only 9 residues actually contact the TCR in both scD10-CA–I-Ak and HA1.7-HA-Dr1 structures. Fig. 3A shows the peptides from four known TCR–pMHC complex structures. The top and bottom panels represent peptides from two pMHCII and two pMHCI, respectively. They are overlaid based on the superposition of the β-sheet platform of the MHC molecules, although MHC molecules are not shown here.
Comparison of CD4–pMHCII versus CD8–pMHCI interactions
The adaptive immune response depends on the specific recognition by a TCR of a pMHC as well as the interaction to the membrane proximal domain of this same pMHC with a CD8 or CD4 co-receptor (CD8 in the case of pMHCI and CD4 in the case of pMHCII) (Reinherz et al., 1983, Kruisbeek et al., 1985, Marrack and Kappler, 1986, Janeway, 1992, Wang and Reinherz, 2000). How TCR and the co-receptor coordinate this bidentate interaction and subsequent downstream signaling is of particular interest.
A ternary TCR–pMHCII–CD4 complex model
To date, there is no ternary complex structure of the TCR–pMHC–co-receptor. Since, CD8α has a long stalk region of more than 40 residues, which is thought to be a highly extended, mucin-like structure, it is difficult to envisage how, or if, the TCR and the entire extracellular fragment of CD8 interact while making contact with the same pMHCI molecule. On the other hand, the extracellular segment of CD4 is composed of four Ig-like domains, and that structure is relatively rigid (Wu et al., 1997
Thymic selection
TCRs are generated in the thymus through a recombinatorial mechanism involving rearrangement of TCR α and β genes, thereby creating a diverse array of receptor specificities (reviewed in Davis and Bjorkman, 1988). Thymocytes bearing TCRs useful to the organism are maintained whereas those displaying potentially harmful autoreactive specificities are deleted. The process termed positive selection enriches for thymocytes with valuable TCR specificities, i.e. ones recognizing foreign peptides
Acknowledgements
This work was supported by NIH Grants GM56008 to J-H.W. and AIl9807 to ELR. We thank Drs. Pedro Reche for compilation and comparison of MHCII-bound peptides and Linda Clayton for review of the manuscript.
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