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

ABSTRACT: 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.

SUBMITTER: Li J

PROVIDER: S-EPMC8995031 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Li Jing J Zaslavsky Maxim M Su Yapeng Y Guo Jing J Sikora Michael J MJ van Unen Vincent V Christophersen Asbjørn A Chiou Shin-Heng SH Chen Liang L Li Jiefu J Ji Xuhuai X Wilhelmy Julie J McSween Alana M AM Palanski Brad A BA Mallajosyula Venkata Vamsee Aditya VVA Bracey Nathan A NA Dhondalay Gopal Krishna R GKR Bhamidipati Kartik K Pai Joy J Kipp Lucas B LB Dunn Jeffrey E JE Hauser Stephen L SL Oksenberg Jorge R JR Satpathy Ansuman T AT Robinson William H WH Dekker Cornelia L CL Steinmetz Lars M LM Khosla Chaitan C Utz Paul J PJ Sollid Ludvig M LM Chien Yueh-Hsiu YH Heath James R JR Fernandez-Becker Nielsen Q NQ Nadeau Kari C KC Saligrama Naresha N Davis Mark M MM

Science (New York, N.Y.) 20220415 6590

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 ele ...[more]

PMID: 35258337

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Project description:IntroductionRegulatory CD8 T cells (CD8 Treg) are responsible for the selective killing of self-reactive and pathogenic CD4 T cells. In autoimmune disease, CD8 Treg may accumulate in the peripheral blood but fail to control the expansion of pathogenic CD4 T cells that subsequently cause tissue destruction. This CD8 Treg dysfunction is due in part to the expression of inhibitory killer immunoglobulin-like receptors (KIR; KIR2DL isoforms [KIR2DL1, KIR2DL2, and KIR2DL3]); these molecules serve as autoimmune checkpoints and limit CD8 Treg activation.MethodsHere we describe the pre-clinical characterization of MTX-101, a bispecific antibody targeting inhibitory KIR and CD8. Using human peripheral blood mononuculear cells (PBMC) derived from healthy donors and autoimmune patients, humanized mouse models, and human derived tissue organoids, we evaluated the molecular mechanisms and functional effects of MTX-101.ResultsBy binding to KIR, MTX-101 inhibited KIR signaling that can restore CD8 Treg ability to eliminate pathogenic CD4 T cells. MTX-101 bound and activated CD8 Treg in human peripheral blood mononuclear cells (PBMC), resulting in increased CD8 Treg cytolytic capacity, activation, and prevalence. Enhancing CD8 Treg function with MTX-101 reduced pathogenic CD4 T cell expansion and inflammation, without increasing pro-inflammatory cytokines or activating immune cells that express either target alone. MTX-101 reduced antigen induced epithelial cell death in disease affected tissues, including in tissue biopsies from individuals with autoimmune disease (i.e., celiac disease, Crohn's disease). The effects of MTX-101 were specific to autoreactive CD4 T cells and did not suppress responses to viral and bacterial antigens. In a human PBMC engrafted Graft versus Host Disease (GvHD) mouse model of acute inflammation, MTX-101 bound CD8 Treg and delayed onset of disease. MTX-101 induced dose dependent binding, increased prevalence and cytolytic capacity of CD8 Treg, as well as increased CD4 T cell death. MTX-101 selectively bound CD8 Treg without unwanted immune cell activation or increase of pro-inflammatory serum cytokines and exhibited an antibody-like half-life in pharmacokinetic and exploratory tolerability studies performed using IL-15 transgenic humanized mice with engrafted human lymphocytes, including CD8 Treg at physiologic ratios.ConclusionCollectively, these data support the development of MTX-101 for the treatment of autoimmune diseases.

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

Publications

KIR<sup>+</sup>CD8<sup>+</sup> T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.

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