Graduate student UMass Chan Med. Sch., United States
Disclosure(s):
Priya Hegde: No financial relationships to disclose
Introduction/Rationale: Autoimmune uveitis (AU) is a potentially blinding ocular inflammatory disorder that can be modeled in mice (Experimental Autoimmune Uveitis). While AU requires chronic treatment to preserve vision and prevent relapse, EAU mice do not spontaneously relapse. We previously identified Tregs that are induced during EAU in an adenosine 2A receptor (A2aR)-dependent manner and protect against EAU relapse. Of note, we also found A2aR stimulation failed to induce Tregs in uveitis patients. Following reports of death receptor 3 (DR3)-mediated Treg expansion in other inflammatory models, we asked if DR3 sustains A2aR-dependent Tregs in EAU.
Methods: Wildtype or A2aR-/- EAU mice were treated with a DR3 agonist (4C12) at peak disease and disease severity was monitored by Fundus exam until resolution. Separately, DR3+ Tregs in post-EAU eyes of CD4-CreERT2; A2aRfl/fl EAU mice were quantified by flow cytometry. The role of DR3 in Treg survival was assessed by treating ocular antigen-primed T cells with 4C12 in vitro and identifying surviving cells by flow cytometry. The function of DR3-expanded cells was assessed by isolating and adoptively transferring primed T cells from 4C12 or vehicle-treated mice that were immunized with ocular antigen.
Results: We demonstrate that DR3 agonism during peak EAU reduces disease severity in A2aR-/- mice, and show a CD4 T cell-intrinsic dependence on A2aR for the accumulation of DR3+ Tregs in the eye at peak EAU. Additionally, we find that in vitro and in vivo DR3 stimulation promotes the accumulation of functionally suppressive Tregs.
Conclusion: Taken together, our findings identify a role for DR3 in promoting Treg accumulation during EAU and provide mechanistic insight into how A2aR-dependent Tregs are maintained.
