Friday, 1 November 2013

T cell activation how a response to a bacteria could stimulate autoimmunity

Sethi DK, Gordo S, Schubert DA, Wucherpfennig KW. Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop. Nat Commun. 2013 Oct;4:2623. doi: 10.1038/ncomms3623.

Self-reactive CD4 T cells are thought to have a central role in the pathogenesis of many chronic inflammatory human diseases. Microbial peptides can activate self-reactive T cells, but the structural basis for such crossreactivity is not well understood. The Hy.1B11 T cell receptor (TCR) originates from a patient with multiple sclerosis and recognizes the self-antigen myelin basic protein. Here we report the structural mechanism of TCR crossreactivity with two distinct peptides from human pathogens. The structures show that a single TCR residue (CDR3α F95) makes the majority of contacts with the self-peptide and both microbial peptides (66.7-80.6%) due to a highly tilted TCR-binding topology on the peptide-MHC surface. Further, a neighbouring residue located on the same TCR loop (CDR3α E98) forms an energetically critical interaction with the MHC molecule. These data show how binding by a self-reactive TCR favors crossreactivity between self and microbial antigens.

T cells see their targets as short linear peptides of about 8-9 (CD8 T cells) and 13 (CD4 T cells) amino acids, which are the building blocks of proteins. Some of the amino acids bind to pockets in the major histocompatibility complex and others stick up and are recognized by T cells so in a sequence the T cell only recognises a few of them and so the rest may not be critical in the recognition process therefore a T cell that can recognise a microbe may sometimes react against ones own tissues.


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