Peptide register shifting within the MHC groove: theory becomes reality

• Published in: Molecular immunology 2004-02, Vol.40 (14), p.1033-1039
• Main Authors: Bankovich, Alexander J., Girvin, Andrew T., Moesta, Achim K., Garcia, K.Christopher
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Autoimmunity - immunology; Frameshifting; Histocompatibility Antigens - immunology; Histocompatibility Antigens - metabolism; Humans; MHC; Peptides - immunology; Peptides - metabolism; Peptide–MHC; Protein Binding; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - immunology; Register; Register shifting; T cell degeneracy; T cell recognition; T-Lymphocytes - immunology
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2003.11.016

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. 170 (1989) 1609; 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.