Human KIR+ CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19

Abstract

Previous reports show a small subset of CD8+ T cells expressing Ly49 proteins in mice can suppress autoimmunity in a model of demyelinating disease. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various human autoimmune diseases. Increased KIR+ CD8+ T cells in the gut also correlate with disease activity in Celiac disease (CeD) patients. Moreover, KIR+ CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from CeD patients’ leukocytes in vitro. Together with gene expression data, this shows that these cells are the likely equivalent of the mouse Ly49+ CD8+ T cells. Furthermore, we observe elevated levels of KIR+ CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Single-cell RNA and parallelized TCR sequencing reveals that expanded KIR+ CD8+ T cells from these different diseases and healthy subjects display shared phenotypes and similar T cell receptor sequences. Selective ablation of the murine counterpart in virus-infected mice leads to exacerbated autoimmunity developed after infection. These results characterize a regulatory CD8+ T cell subset in humans which we hypothesize functions to control pathogenic cells in autoimmune and infectious diseases, with important implications for the cellular dynamics and possible therapeutic approaches to suppress unwanted autoimmunity. Supported by National Institutes of Health U19-AI057229 Howard Hughes Medical Institute Stanford Diabetes Research Center (P30DK116074)

Activation and clonal expansion of CD8+T cells in patients with anti-NMDAR encephalitis revealed by single-cell RNA sequencing analysis

“…4H). Similarly, clonal CD8 + T cells in the blood of patients exhibited upregulation of genes linked to cytotoxicity (GZMH, GZHB and PRF1) and cell trafficking (CX3CR1 and ITGB1) [33] (Fig. 4F and Fig.…”

“…In the CSF of patients, CD8 + T cells with TCR clones exhibited upregulation of genes associated with cytotoxicity (GZMA and GZMK) [30] and cell trafficking (CCL5, CCL4, CCL4L2 and ITGB1) [33], while showing downregulation of genes associated with naïve/memory (CCR7 and SELL) (Fig. 4G and Fig.…”

“…In this study, we investigated the presence and characteristics of a regulatory subset of CD8 + T cells known as KIR + CD8 + T cells in NMDAR-E patients. These cells express killer-cell immunoglobulin-like receptors (KIRs), which possess inhibitory functions contributing to their regulatory role [33,34]. Importantly, KIR + CD8 + T cells have been shown to suppress pathogenic CD4 + T cells in autoimmune and infectious diseases [33].…”

“…These cells express killer-cell immunoglobulin-like receptors (KIRs), which possess inhibitory functions contributing to their regulatory role [33,34]. Importantly, KIR + CD8 + T cells have been shown to suppress pathogenic CD4 + T cells in autoimmune and infectious diseases [33].…”

Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells

“…In a model where KIR3DL3 is induced as an immune checkpoint, this ablation could bias CD28H + lymphocytes toward continued activation. Recently, a population of KIR + CD8 + regulatory T cells was identified at elevated levels in patients with autoimmune diseases ( 101 ). This population has been likened to Ly49 + CD8 + T cells, which are capable of suppressing pathogenic CD4 + T cells in a murine model of systemic lupus erythematosus–like disease ( 102 ).…”