Peptide register shifting within the MHC groove: theory becomes reality.
Degeneracy in immune recognition is usually thought of in terms of the astonishing ability of the T cell receptor to recognize an enormously diverse array of peptides bound to major histocompatibility complex (MHC) molecules. However, in this essay we discuss an alternative aspect of degeneracy in T cell recognition: the notion that peptides can assume different "registers" in the groove of a single MHC molecule, as first suggested and demonstrated by Sercarz and co-workers (reviewed in [J. autoimmun. 16 (2001) 201]). There is now abundant evidence, derived from functional, biochemical and structural studies, that single peptides can assume alternative, unpredictable binding registers by frameshifting within the MHC groove [Nat. Immunol. 3 (2002) 175;; J. Exp. Med. 187 (1998) 1505; J. Mol. Biol. 304 (2000) 177; Biochemistry 38 (1999) 16663; J. Exp. Med. 197 (2003) 1391; Eur. J. Immunol. 19 (1989) 681]. Hence, register shifting adds an additional dimension to the concept of degeneracy. In fact, the possibility of register shifting multiplies the universe of peptide-MHC (pMHC) surfaces that a TCR must recognize by an unknown, perhaps enormous factor. Register shifting also has profound implication for autoimmunity: (1) as a mechanism to "mask" autoantigenic epitopes during thymic education [Immunol. Rev. 169 (1999) 147; Immunity 17 (2002) 83]; and (2) as a possible source for pMHC complexes capable of molecular mimicry.
Bankovich
Alexander J
AJ
Department of Microbiology & Immunology, Stanford University School of Medicine, Fairchild D319, Stanford, CA 94305-5124, USA.
Girvin
Andrew T
AT
Moesta
Achim K
AK
Garcia
K Christopher
KC
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D006649:Histocompatibility Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell