An Immunologically Privileged Retinal Antigen Elicits Tolerance

Abstract

Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.

Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity

“…Our findings agree with earlier reports that thymic deletion of autoreactive T cells is a dominant mechanism of tolerance to retinal Ags including IRBP (8,12) and that this is dependent on AIRE (13)(14)(15). Loss of AIRE-dependent expression of rHEL accelerates the stage of onset of disease, presumably by increasing the release of autoreactive T cells into the periphery.…”

“…It is not known to what extent this is due to the interplay of background modifier genes or transgene and promoter-specific differences in Ag expression. In addition individual variation in disease susceptibility may be due to different levels of Ag expression in the thymus (51) and strain-specific resistance to IRBP has been shown to correlate with the level of thymically expressed IRBP (8,12).…”

“…Recent studies have suggested a role for Tregs in the control of EAU (8,10,11) and examination of CD4 ϩ T cells from TCRrHEL double-transgenic mice revealed a small number of CD45RB low CD25 ϩ cells, which were enriched as a fraction of total CD4 ϩ T cells (Fig. 4A) but not increased in absolute numbers of clonotype-specific CD4 ϩ CD25 ϩ or Foxp3 ϩ CD4 ϩ CD25 ϩ compared with TCR controls (Fig.…”

“…The failure to delete autoreactive T cells in AIRE-knockout mice (AIRE-KO) leads to multiple organ-specific autoimmunity which includes retinal inflammation and anti-retinal Abs (13,14). The fact that uveoretinitis is blocked in animals that are deficient in both AIRE and endogenous IRBP suggests that IRBP-specific T cells play an essential role in disease (8,15).…”

“…In addition, the transplantation of thymi from IRBP-deficient mice into wild-type (WT) recipients exacerbates IRBP-induced EAU. This is due to the escape of autoreactive T cells from the transplanted organ and possibly due to a failure to induce IRBP-specific Tregs (8). Thymic expression of tissue-specific Ags in medullary epithelial cells, which mediate the subsequent deletion of autoreactive T cells, is largely controlled by the autoimmune transcriptional regulator AIRE (13,14).…”