Abstract
Purpose :
Experimental autoimmune uveitis (EAU) is used to gain a better understanding of human autoimmune uveitis. EAU-resolution is in part due to emergence of ocular antigen specific regulatory T cells (Tregs) that express T cell Immunoreceptor with Ig and ITIM domains (TIGIT). We have previously published that post-EAU TIGIT+ Tregs are distinct from post-EAU PD-1+ Tregs, and that Treg induction of PBMCs from uveitis patients induces significantly fewer TIGIT+ Tregs compared to controls. The role for TIGIT on Th17 cells over the course of EAU is not well understood.
Methods :
IL-17-GFP and Foxp3-GFP reporter mice given TIGIT blocking antibody (Ab) at the onset of EAU and post-EAU mice were reimmunized for EAU. Flow cytometry analysis of TIGIT expression on Th17 and Tregs was done at the onset of EAU. Slit lamp examination and infiltration of Th17 and Tregs into the eye was done throughout disease and following reimmunization.
Results :
We observed Th17 cells emerge in the eye beginning at the onset of EAU and diminish as EAU resolved. At the onset of EAU flow cytometry analysis of ocular T cells revealed 2-5-fold more TIGIT+ T cells in the FoxP3 compartment compared to the Th17 compartment. The reporter mice confirmed a persistence of Tregs in the eye compared to a decrease in Th17 cells as resolution of EAU occurred. Mice administered TIGIT blocking Ab showed no difference in the course of disease compared with control EAU mice. Reimmunization of EAU resulted in a significant increase in EAU of mice that received TIGIT blocking Ab compared to control EAU mice that received isotype Ab. Reimmunization of reporter mice that received TIGIT Ab showed diminished Tregs, and an increase of Th17 cells in the eye. In contrast, control reporter mice that received isotype had an increase in Tregs, and a decrease in Th17 cells in the eye.
Conclusions :
This work suggests that TIGIT is needed for the induction of Tregs that emerge and persist in the eye over the course and resolution of EAU. Additionally, TIGIT signaling limits the migration of Th17 cells into the eye as resolution of EAU occurs. We also provide evidence that relapse of EAU may be due to an expansion of Th17 cells in the eye, and this expansion may be limited by TIGIT-dependent Tregs. The implication of this work is that TIGIT signaling may be an important mechanism that provides resistance to relapsing autoimmune uveitis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.