CD8 T cell exhaustion is reduced in subjects with autoimmune-associated DR4 risk alleles

Abstract

Abstract Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer and better outcome in autoimmunity. However, factors contributing to reduced TEX in the context of autoimmunity are not well understood. Here, we identify co-expression of TIGIT and KLRG1 as a broad identifier of human TEX: TIGIT+KLRG1+ CD8 memory T cells share EOMES signature genes in healthy controls (HC), T1D and Rheumatoid Arthritis (RA) subjects, are increased with age and in chronic viral-specific cells, and are hyporesponsive (reduced proliferation and cytokine production) in vitro. We applied this inclusive, sample sparing and high throughput measure of TEX to larger longitudinal and autoimmune cohorts. Consistent with a genetic determinant, TEX are stable within HC and T1D individuals (Interclass correlation coefficient=92.0 and 83.7%, respectively), but display high interindividual variation (range 0.37–28.47 of CD8). In a large cohort of HC and RA subjects (n>100/cohort), lower levels of EOMES modules and TEX were associated with the HLA Class II DR4 autoimmune risk allele, regardless of disease status. While the DR4 locus is complex, these findings suggest that TEX may be indirectly influenced by APC or CD4 T cell help. Moreover, therapeutic modulation of TEX may differ in DR4 risk and non risk subjects, with implications for precision medicine. Supported by grants from the NIH (R01 AI141952, R21 5R21AR073508-02) and JDRF.