Alana M. McSween

In this work, we find that CD8 ⁺ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49 ⁺ CD8 ⁺ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 ⁺ T cells efficiently eliminated pathogenic gliadin-specific CD4 ⁺ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR ⁺ CD8 ⁺ T cells, but not CD4 ⁺ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49 ⁺ CD8 ⁺ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8 ⁺ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

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 equivalent of the Ly49 family, in the blood and inflamed tissues of various 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 this correlates 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. One-Sentence Summary: Here we identified KIR ⁺ CD8 ⁺ T cells as a regulatory CD8 ⁺ T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4 ⁺ T cells.

A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αβ T cell staining reagent platform, with each maxi-ferritin “spheromer” displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a “memory” phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8⁺ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.