Reduced CD8 T Cell Exhaustion in DR4 Risk Subjects is Selectively Augmented with Abatacept in RA

Exhausted CD8 T cells (T_EX) are associated with worse outcome in cancer yet better outcome in autoimmunity. However, factors contributing to reduced T_EX in autoimmunity are not well understood. Here, we identify co-expression of TIGIT and KLRG1 as identifiers of human T_EX. TIGIT+KLRG1+ CD8 memory T cells share EOMES signature genes in healthy controls (HC), type 1 diabetes, 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 measure of T_EX to larger longitudinal and autoimmune cohorts. Consistent with a genetic determinant, T_EX are stable within HC (within-individual mean range in frequency 6.5% (95% CI: 5.6-7.4%)) but vary between individuals (inter-individual mean frequency 4.2-59.8%) resulting in a high intraclass correlation coefficient of 92.0%.  In a large cohort of HC and RA subjects (n >90/cohort), lower levels of EOMES transcriptional modules and T_EX cells were associated with RA-associated HLA risk alleles (primarily DR4), regardless of disease status. In a treatment cohort, an increase in T_EX following treatment was more prevalent in RA HLA risk subjects (11/16, 69%, p=0.0043) than non-risk subjects (4/10, 40%,p= ns) treated with abatacept; no change in T_EX was observed with adalimumab (anti-TNF). The HLA association and selective modulation with abatacept suggests that T_EX may be indirectly influenced by APC or T cell help, that is blocked by abatacept. Moreover, targeting factors that increase T_EX may be more effective in HLA risk subjects, a step towards personalized medicine.