KIR + CD8 + T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19

• Published in: Science (American Association for the Advancement of Science) Vol. 376; no. 6590; p. eabi9591
• Main Authors: Li, Jing, Zaslavsky, Maxim, Su, Yapeng, Guo, Jing, Sikora, Michael J., van Unen, Vincent, Christophersen, Asbjørn, Chiou, Shin-Heng, Chen, Liang, Li, Jiefu, Ji, Xuhuai, Wilhelmy, Julie, McSween, Alana M., Palanski, Brad A., Mallajosyula, Venkata Vamsee Aditya, Bracey, Nathan A., Dhondalay, Gopal Krishna R., Bhamidipati, Kartik, Pai, Joy, Kipp, Lucas B., Dunn, Jeffrey E., Hauser, Stephen L., Oksenberg, Jorge R., Satpathy, Ansuman T., Robinson, William H., Dekker, Cornelia L., Steinmetz, Lars M., Khosla, Chaitan, Utz, Paul J., Sollid, Ludvig M., Chien, Yueh-Hsiu, Heath, James R., Fernandez-Becker, Nielsen Q., Nadeau, Kari C., Saligrama, Naresha, Davis, Mark M.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 15.04.2022; American Association for the Advancement of Science
• Subjects: Ablation; Animals; Antiviral drugs; Autoimmune Diseases; Autoimmunity; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Celiac disease; Control Groups; Coronaviruses; COVID-19; Cytolytic activity; Cytotoxicity; Depletion; Equivalence; Experimental allergic encephalomyelitis; Functionals; Gene sequencing; Gliadin; Glycoproteins; Humans; Immunoglobulin-like receptors; Immunoglobulins; Immunological tolerance; Immunology; In vitro methods and tests; Infections; Infectious diseases; Inflammation; Influenza; Killer cell immunoglobulin-like receptors; Leukocytes; Long COVID; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; Multiple sclerosis; Myelin; Negative feedback; Patients; Phenotypes; Receptors; Receptors, KIR; Respiratory diseases; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; T cell receptors; T-Lymphocytes, Regulatory; Toxicity; Transcription; Vasculitis; Viral diseases; Viral infections; Viruses
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abi9591

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. Ly49 + CD8 + T cells are a subset of CD8 + T cells that show immunoregulatory activity in mice. Li et al . report the existence of a similar CD8 + T cell subset in humans that expresses killer cell immunoglobulin-like receptors (KIRs), a functional parallel of the mouse Ly49 family (see the Perspective by Levescot and Bensussan). These cells, which can suppress self-reactive CD4 + T cells, were more abundant in patients with autoimmune conditions such as celiac disease, multiple sclerosis, and lupus, as well as in patients infected with influenza virus or severe acute respiratory syndrome coronavirus 2. When mice selectively deficient in Ly49 + CD8 + T cells were infected with viruses, they showed normal antiviral immune responses but eventually developed symptoms of autoimmune disease. KIR + CD8 + T cells may therefore be an important therapeutic target for the control of autoimmune diseases such as “long COVID” that emerge after viral infections. —STS Regulatory CD8 + T cells act to suppress pathogenic T cells in autoimmune and infectious diseases in mice and humans.