Reduced CD8 T cell exhaustion in DR4 risk subjects is selectively augmented with therapy [CD8s]

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. However, factors contributing to reduced TEX in autoimmunity are poorly understood. We use two genetically related autoimmune diseases, type 1 diabetes (T1D) and rheumatoid arthritis (RA), to explore these factors. We identify a common human peripheral blood TIGIT+KLRG1+ CD8 TEX population: TIGIT+KLRG1+ CD8 TEX of healthy controls (HC), T1D, and rheumatoid arthritis (RA) subjects share EOMES signature genes, are increased with age and in chronic viral-specific cells and are hyporesponsive in vitro. Consistent with a genetic determinant, TIGIT+KLRG1+ TEX are stable within but vary between individuals. In HC and RA subjects (n>100/cohort), lower levels of EOMES transcriptional modules and TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and CMV seropositivity. TIGIT+KLRG1+ TEX significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig); no change in TIGIT+KLRG1+ TEX was observed with adalimumab (anti-TNF) therapy. The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept. KLRG1+/TIGIT+ partially exhausted CD8 T-cells and KLRG1-/TIGIT- CD8 T-cells were profiled from healthy individuals, individuals with type 1 diabetes, and individuals with renal cell carcinoma (RCC). Gene expression of KLRG1+/TIGIT+ partially exhausted CD8 T-cells from healthy individuals specific for flu or CMV antigens were also sorted using tetramers and profiled.