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
Volume
205
Issue
7
First Page
1763
Last Page
1777
ISSN
1550-6606
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.
Recommended Citation
Ye C,
Low BE,
Wiles MV,
Brusko T,
Serreze DV,
Driver J.
CD70 Inversely Regulates Regulatory T Cells and Invariant NKT Cells and Modulates Type 1 Diabetes in NOD Mice. J Immunol 2020 Oct 1; 205(7):1763-1777
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.