Pro-inflammatory self-reactive T cells are found within murine TCR-αβ+CD4−CD8−PD-1+ cells

TCR-αβ⁺ double negative (DN) T cells (CD3⁺TCR-αβ⁺CD4⁻CD8⁻NK1.1⁻CD49b⁻) represent a minor heterogeneous population in healthy humans and mice. These cells have been ascribed pro-inflammatory and regulatory capacities and are known to expand during the course of several autoimmune diseases. Importantly, previous studies have shown that self-reactive CD8⁺ T cells become DN after activation by self-antigens, suggesting that self-reactive T cells may exist within the DN T cell population. Here, we demonstrate that PD-1 expression in unmanipulated mice identifies a subset of DN T cells with expression of activation-associated markers and a phenotype that strongly suggests they are derived from self-reactive CD8⁺ cells. We also found that, within DN T cells, the PD-1⁺ subset generates the majority of pro-inflammatory cytokines. Finally, using a TCR-activation reporter mouse (Nur77-GFP), we confirmed that in the steady state PD-1⁺ DN T cells engage endogenous antigens in healthy mice. In conclusion, we provide evidence that indicates that the PD-1⁺ fraction of DN T cells represents self-reactive cells.

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