Interconnected lineage trajectories link conventional and natural killer (NK)-like exhausted CD8 + T cells beneficial in type 1 diabetes.

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.