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

Abstract

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.