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Distinct Natural Killer (NK)-like CD57+ and PD-1+ CD8+ exhausted-like T cell populations (Tex) have both been linked to beneficial immunotherapy response in autoimmune type 1 diabetes (T1D) patients. The origins and relationships between these cell types are poorly understood. Here we show that while PD-1+ and CD57+ Tex populations are epigenetically similar, CD57+ Tex cells display unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also show reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex show unappreciated gene expression heterogeneity and share clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex-like populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment. RNA-sequencing data from NK-like CD57+ and PD-1+ CD8+ exhausted-like T cell populations linked to beneficial immunotherapy response in autoimmune patients suggest shared clonal relationships with each other and with common precursor populations. [ABSTRACT FROM AUTHOR]

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT+KLRG1+ TEX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT+KLRG1+ TEX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT+KLRG1+ CD8 TEX 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+ TEX 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+ TEX 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 TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept. [ABSTRACT FROM AUTHOR]

Following acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. Here we demonstrate that Tfh and Th1 lineages acquire distinct de novo DNA methylation programs that are preserved into memory. Using whole genome methylation analyses and deletion of DNA methyltransferase 3a, we found that de novo DNA methylation is required for generating epigenetic programing to enforce lineage commitment and preserve lineage-specific functions during a recall response to infection. Importantly, partial inhibition of de novo methylation using the methyltransferase inhibitor decitabine during priming enhances Tfh cell functionality in primary and secondary responses to viral infection. Together, these findings demonstrate that de novo DNA methylation is critical to balance lineage commitment and functionality of memory CD4+ T cell subsets and reveal novel potential strategies to modulate immune responses to infectious diseases., Summary: Effector Tfh and Th1 cells acquire lineage-specific de novo DNA methylation programs that are required to enforce lineage commitment and preserve functionality of memory Tfh and Th1 cells during the recall response to viral infection.