Transcriptional profiling of human KIR+ and KIR- CD8 T cells by bulk RNA-seq

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalents of the Ly49 family, in the blood and inflamed tissues of various human autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients' leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and correlate with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. Overall design: KIR+ and KIR- CD8 T cells (CD3+CD56-CD8+) were sorted from healthy subjects (N=5), MS (N=3), SLE (N=4) or CeD (N=1) patients and then subjected to RNA-seq analysis. CD8 T cells with high or low expression of KIR2DL3 or KIR3DL1 were sorted from the blood of healthy subjects (N=3) and subjected to RNA-seq analysis.