Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles

Exhausted CD8 T cells (T_EX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT⁺KLRG1⁺ T_EX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT⁺KLRG1⁺ T_EX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT⁺KLRG1⁺ CD8 T_EX population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive in vitro, together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT⁺KLRG1⁺ T_EX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT⁺KLRG1⁺ T_EX was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of T_EX may be more effective in DR4 subjects and T_EX may be indirectly influenced by cellular interactions that are blocked by abatacept.