Lang Philipp A, Crome Sarah Q, Xu Haifeng C, Lang Karl S, Chapatte Laurence, Deenick Elissa K, Grusdat Melanie, Pandyra Aleksandra A, Pozdeev Vitaly I, Wang Ruifeng, Holderried Tobias A W, Cantor Harvey, Diefenbach Andreas, Elford Alisha R, McIlwain David R, Recher Mike, Häussinger Dieter, Mak Tak W, Ohashi Pamela S
Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.
Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
Front Cell Infect Microbiol. 2020 Feb 13;10:36. doi: 10.3389/fcimb.2020.00036. eCollection 2020.
Elucidating key factors that regulate immune-mediated pathology is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8 T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8 T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV. High-dose LCMV infection induced an impaired CD8 T cell response, which coincided with increased NK cell activity during early time points following infection. Notably, we observed increased NKp46 expression on NK cells during infection with higher doses, which resulted in an NK cell dependent suppression of T cells. Accordingly, depletion with antibodies specific for NK1.1 as well as NKp46 deficiency ( mice) could restore CD8 T cell immunity and permitted the induction of diabetes even following infection of RIP-GP mice with high-dose LCMV. Therefore, we identify conditions where innate lymphoid cells can play a regulatory role and interfere with CD8 T cell mediated tissue specific pathology using an NKp46 dependent mechanism.
阐明调节免疫介导病理的关键因素对于开发治疗自身免疫性疾病和癌症的改进策略至关重要。病毒感染后，自然杀伤细胞（NK细胞）可对CD8 T细胞发挥调节功能。在此我们表明，虽然低剂量淋巴细胞性脉络丛脑膜炎病毒（LCMV-WE）能轻易在β胰岛细胞上表达LCMV糖蛋白的小鼠（RIP-GP小鼠）中诱导强烈的CD8 T细胞反应和糖尿病，但高剂量LCMV感染后不会出现高血糖。高剂量LCMV感染诱导CD8 T细胞反应受损，这与感染后早期NK细胞活性增加相一致。值得注意的是，我们观察到高剂量感染期间NK细胞上NKp46表达增加，这导致NK细胞依赖性的T细胞抑制。因此，用NK1.1特异性抗体清除以及NKp46缺陷（小鼠）即使在RIP-GP小鼠感染高剂量LCMV后也能恢复CD8 T细胞免疫并引发糖尿病。因此，我们确定了先天性淋巴细胞可通过依赖NKp46的机制发挥调节作用并干扰CD8 T细胞介导的组织特异性病理的条件。
