The structural interactions between T cell receptors and MHC-peptide complexes place physical limits on self-nonself discrimination.
The activation and expansion of T cells in an antimicrobial immune response is based on the ability of T cell receptors (TCR) to discriminate between MHC-bound peptides derived from different microbial agents as well as self-proteins. However, the specificity of T cells is constrained by the limited number of peptide side chains that are available for TCR binding. By considering the structural requirements for peptide binding to MHC molecules and TCR recognition of MHC-peptide complexes, we demonstrated that human T cell clones could recognize a number of peptides from different organisms that were remarkably distinct in their primary sequence. These peptides were particularly diverse at those sequence positions buried in pockets of the MHC binding site, whereas a higher degree of similarity was present at a limited number of peptide residues that created the interface with the TCR. These T cell clones had been isolated from multiple sclerosis patients with human myelin basic protein, demonstrating that activation of such autoreactive T cells by microbial peptides with sufficient structural similarity may contribute to the disease process. Similar findings have now been made for a variety of human and murine T cell clones, indicating that specificity and cross-reactivity are inherent properties of TCR recognition. The observations that particular TCR are highly sensitive to changes at particular peptide positions but insensitive to many other changes in peptide sequence are not contradictory, but rather the result of structural interactions in which a relatively flat TCR surface contacts a limited number of side chains from a peptide that is deeply embedded in the MHC binding site.
Wucherpfennig
K W
KW
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. wucherpf@mbcrr.harvard.edu
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D015802:HLA-DR2 Antigen / Q000737:chemistry; D006801:Humans; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D004676:Myelin Basic Protein / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D015802:HLA-DR2 Antigen; D046912:Multiprotein Complexes; D004676:Myelin Basic Protein; D010455:Peptides; D011948:Receptors, Antigen, T-Cell