Purchase this article with an account.
Darren J Lee, Dawei Wang, Fauziyya Muhammad; Anti-Uveitic Treg Cells Function Through PD-1 and a Subset of Uveitis Patients Express PD-1 with A2Ar Stimulation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):535.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Resolution of experimental autoimmune uveoretinitis (EAU) is marked by antigen specific regulatory immunity in the spleen. This post-EAU regulatory immunity requires adenosine 2A (A2Ar) expression on post-EAU Treg cells that are PD-1+PD-L1+Nrp-1-CD25+CD4+ (PD-1 Tregs). These Tregs suppress Teff cells through PD-1, but it has not been demonstrated if the suppression is mediated by signaling through the T cell or APC. It is also not known if PD-1 is expressed on T cells from uveitis patients or if stimulation of A2Ar affects PD-1 expression.
Spleen cells from post-EAU mice (80-90 days after immunization) were collected, restimulated with IRBPp 1-20 (IRBP), and sorted for PD-1 Tregs. Treg suppression of Teff through PD-1 and Treg induction of regulatory APC was determined by co-culturing Tregs with IRBP-specific primed T cells (responder T cells) or spleen APC with and without PD-1 blocking antibody. Co-cultured APC were then used to activate responder T cells. Treg functionality was determined by transferring responder T cells to recipient mice immunized for EAU. T cells from two groups of uveitis patients were assayed for PD-1 expression following A2Ar stimulation. The active group (UA) had inflammation within one year before the time of collection and if the last time of inflammation was more than a year the patient was considered suppressed (US).
Mice that received responder T cells activated with post-EAU Tregs or with regulatory APC induced by post-EAU Tregs showed significant suppression of EAU. Moreover, the post-EAU Tregs were unable to induce regulatory APC or suppress responder T cells when PD-1 blocking antibody was present. PD-L1 expression was observed on all CD4+CD25+ T cells and trended higher in healthy compared to uveitis patients. FoxP3 expression was unchanged with A2Ar stimulation in healthy volunteers (n=6) but increased by 50% in roughly 30% of uveitis patients (n=36) and PD-1 up-regulation occurred in 20% of the uveitis patients.
These results show that post-EAU Tregs suppress uveitis through the PD-1/PD-L1 pathway on both APC and Teff cells. Importantly, through stimulation of A2Ar it was possible to up-regulate PD-1 on T cells from a subset of uveitis patients. Therefore, A2Ar stimulation may be an effective treatment for a subset of uveitis patients and this may function through the PD-1 pathway.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
This PDF is available to Subscribers Only