NK Cells Regulate CD8+ T Cell Mediated Autoimmunity.

Philipp A Lang,Tobias A W Holderried,Dieter Häussinger,Melanie Grusdat,Alisha R Elford,Elissa K Deenick,Vitaly I Pozdeev,David R Mcilwain,Sarah Q Crome,Aleksandra A Pandyra,Ruifeng Wang,Karl S Lang,Andreas Diefenbach,Pamela S Ohashi,Tak W Mak,Mike Recher,Harvey Cantor,Laurence Chapatte,Haifeng C Xu

doi:10.3389/fcimb.2020.00036

Abstract

Elucidating key factors that regulate immune-mediated pathology in vivo 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 (Ncr1gfp/gfp 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.

Highlights

Efforts have been made to understand ways to promote the induction of CD8+ T cell immunity as an avenue to improve tumor immune therapy, promote viral clearance, or treat autoimmune diseases
We found that rat insulin promotor (RIP)-GP mice infected with a high dose of LCMV showed a modest reduction in CD8+ T cell immune responses and did not develop diabetes
In order to determine whether different infectious doses of LCMV can influence the induction of CD8+ T cell mediated immune pathology, RIP-GP mice were infected intravenously with the LCMV WE strain ranging from 103 to 105 plaqueforming units (PFU) per mouse

Summary

Introduction

Efforts have been made to understand ways to promote the induction of CD8+ T cell immunity as an avenue to improve tumor immune therapy, promote viral clearance, or treat autoimmune diseases. Studies have demonstrated that innate lymphoid cells including NK1.1+ cells in mice or CD56+ cells in humans have displayed immune-regulatory functions and can play an important role in limiting CD8+ T cell responses (Crome et al, 2013). ILCs/NK cells regulate CD8+ T cell anti-viral immunity (Su et al, 2001; Lu et al, 2007; Lang et al, 2012; Waggoner et al, 2012), and CD8+ T cell antitumor immunity (Iyori et al, 2011; Iraolagoitia et al, 2016; Crome et al, 2017; Picard et al, 2019)

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Conclusion