Title

CD70 Inversely Regulates Regulatory T Cells and Invariant NKT Cells and Modulates Type 1 Diabetes in NOD Mice.

Document Type

Article

Publication Date

10-1-2020

Keywords

JMG, JAXCC

JAX Source

J Immunol 2020 Oct 1; 205(7):1763-1777

PMID

32868408

DOI

https://doi.org/10.4049/jimmunol.2000148

Grant

DK46266,DK95735,OD020351

Abstract

The CD27-CD70 costimulatory pathway is essential for the full activation of T cells, but some studies show that blocking this pathway exacerbates certain autoimmune disorders. In this study, we report on the impact of CD27-CD70 signaling on disease progression in the NOD mouse model of type 1 diabetes (T1D). Specifically, our data demonstrate that CD70 ablation alters thymocyte selection and increases circulating T cell levels. CD27 signaling was particularly important for the thymic development and peripheral homeostasis of Foxp3+Helios+ regulatory T cells, which likely accounts for our finding that CD70-deficient NOD mice develop more-aggressive T1D onset. Interestingly, we found that CD27 signaling suppresses the thymic development and effector functions of T1D-protective invariant NKT cells. Thus, rather than providing costimulatory signals, the CD27-CD70 axis may represent a coinhibitory pathway for this immunoregulatory T cell population. Moreover, we showed that a CD27 agonist Ab reversed the effects of CD70 ablation, indicating that the phenotypes observed in CD70-deficient mice were likely due to a lack of CD27 signaling. Collectively, our results demonstrate that the CD27-CD70 costimulatory pathway regulates the differentiation program of multiple T cell subsets involved in T1D development and may be subject to therapeutic targeting.

Comments

The authors are grateful for the assistance of Dr. Yi-Guang Chen for critically reading the manuscript and providing constructive advice. We thank Dr. Michael Clare-Salzler for providing us with NOD.BDC2.5.Foxp3eGFP mice and Celldex Therapeutics for donating the AT-124 Ab.

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