Human thymoproteasome variations influence CD8 T cell selection

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Science Immunology  02 Jun 2017:
Vol. 2, Issue 12, eaan5165
DOI: 10.1126/sciimmunol.aan5165

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Proteasome polymorphisms regulate T cell selection

Activation of CD8 T cells relies on proteasome-processed peptide loading on to class I MHC; this is regulated by a thymus-specific proteasome subunit, β5t, in cortical thymic epithelial cells (cTECs) which promote positive selection of CD8 T cells. Here, Nitta et al. studied the effect of three human variants of β5t by engineering mice that express these isoforms. Expression of these variants resulted in a dose-dependent impairment in positive selection of CD8 T cells, suggesting that all three isoforms are loss-of-function mutations. They link one of the variants, β5t G49S to a higher risk of Sjögren’s syndrome. The studies suggest that by influencing T cell selection, genetic variations in proteasome genes can contribute to disease susceptibility.