Here we described the use and possible therapeutic benefit of Col-Treg, a regulatory T cell–based immunotherapy for the treatment of NIU in mice and the potential for this immunotherapy to be translated in humans. Firstly, characterization results showed that Col-Treg belongs to the type 1 Treg cell subpopulation. The therapeutic benefit of type 1 Treg adoptive transfer has been previously demonstrated in models of skin inflammation,
7 asthma,
8 rheumatoid arthritis,
9 and type-1 diabetes.
35 In all these settings, type 1 Treg homed preferentially to the inflamed tissues, as observed here with a Col-Treg migration in inflamed, but not in healthy eyes. Interestingly, the migration of Col-Treg cells to inflamed eyes correlated to the degree of inflammation at the time of their administration, suggesting that Col-Treg cells might be particularly active in a severe inflammatory context. High expression of LFA-1 and PSGL-1 are likely to be involved in this migration by inducing strong adhesion to the activated vascular endothelium of the inflamed ocular tissues.
36 Indeed, P-selectin and ICAM-1, the respective ligands of PSGL-1 and LFA-1, are known to be present in inflamed eye vascular endothelium in EAU. Together with this capacity to home to inflammatory lesions, antigen-specificity is also a key parameter for type 1 Treg cell efficacy in vivo, allowing them to be effective only in a specific location. Indeed, in inflammatory bowel disease (IBD) models, specificity to ovalbumin has been used to trigger the immunoregulatory function of ovalbumin-specific type 1 Treg (Ova-Treg) cells in the inflamed gut.
7,8 Absence of ovalbumin negates the therapeutic activity of Ova-Treg despite the presence of cells in the inflamed areas, demonstrating that in situ antigen recognition is a crucial step in the mode of action of antigen-specific type 1 Treg–based immunotherapy. Here, collagen II is a constitutive antigen of the eye, with reported higher protein expression in vitreous and weaker signal in retinal epithelium, cornea, and sclera.
23 This pattern of murine collagen type II expression was confirmed in the present study in the EAU model at the peak of disease (
Supplementary Fig. S1). It is postulated that as Col-Treg cells migrate to the inflamed eye, antigen recognition occurs at the ocular level, leading to local Col-Treg activation and bystander suppressive effect. Despite the use of DBA-1 mice, in which only mild EAU can be obtained upon immunization with IRBP peptides, the results from clinical and histologic evaluations show Col-Treg inhibition of uveitis-related changes in the ocular tissues. Here, although Col-Treg administration at day 8 after the first IRBP immunization (1 day after the boost of immunization) cannot be seen as a curative treatment because of lack of clinical symptoms, it shows an inhibition of an ongoing systemic and ocular proinflammatory immune response witnessed by elevated proinflammatory cytokine levels at day 8 of the disease.