T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue.
J Immunol 2020 Oct 15; 205(8):2026-2038
Juvenile Diabetes Research Foundation, DK46266,DK95735,NS054154,OD020351,CA034196
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.
Racine, Jeremy; Chapman, Harry; Doty, Rosalinda A.; Cairns, Brynn; Hines, Timothy J; Tadenev, Abigail L D; Anderson, Laura C.; Green, Torrian L; Dyer, Meaghan E; Wotton, Janine M; Bichler, Zoë; White, Jacqueline K; Ettinger, Rachel; Burgess, Robert W.; and Serreze, David V., "T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue." (2020). Faculty Research 2020. 203.