Allergic conjunctivitis renders CD4⁺ T cells resistant to T regulatory cells and exacerbates corneal allograft rejection

Allergic diseases rob corneal allografts of immune privilege and increase immune rejection. Corneal allograft rejection in BALB/c allergic hosts was analyzed using a short ragweed (SWR) pollen model of allergic conjunctivitis. Allergic conjunctivitis did not induce exaggerated T-cell responses to donor C57BL/6 (B6) alloantigens or stimulate cytotoxic T lymphocyte (CTL) responses. Allergic conjunctivitis did affect T regulatory cells (Tregs) that support graft survival. Exogenous IL-4, but not IL-5 or IL-13, prevented Treg suppression of CD4⁺ effector T cells isolated from naïve mice. However, mice with allergic conjunctivitis developed Tregs that suppressed CD4⁺ effector T-cell proliferation. In addition, IL-4 did not inhibit Treg suppression of IL-4Rα^-/- CD4⁺ T-cell responses, suggesting that IL-4 rendered effector T cells resistant to Tregs. SRW-sensitized IL-4Rα^-/- mice displayed the same 50% graft survival as nonallergic WT mice, that was significantly less than the 100% rejection that occurred in allergic WT hosts, supporting the role of IL-4 in the abrogation of immune privilege. Moreover, exacerbation of corneal allograft rejection in allergic mice was reversed by administering anti-IL-4 antibody. Thus, allergy-induced exacerbation of corneal graft rejection is due to the production of IL-4, which renders effector T cells resistant to Treg suppression of alloimmune responses. The exacerbation of immune rejection of corneal transplants that occurs in mice with allergic conjunctivitis is due to allergen-induced IL-4, which renders immune effector T cells resistant to the inhibitory effects of T regulatory cells.