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K. Cunnusamy, P. W. Chen, J. Y. Niederkorn; Corneal Allograft Survival Requires Interplay Between T Regulatory Cells and Interleukin-17A. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1549.
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This study examined the unique interplay between CD4+CD25+ T regulatory cells (Tregs) and IL-17A that promotes establishment of ocular immune privilege and corneal allograft survival.
BALB/c mice bearing C57BL/6 corneas were injected with anti-IL-17, anti-CD25 or a rat IgG isotype control antibody. CD4+CD25+ Tregs were isolated from graft acceptors 3 weeks post transplantation. Delayed type hypersensitivity (DTH) responses to C57BL/6 alloantigens were measured using an ear-swelling assay. Anterior chamber-associated immune deviation (ACAID) was assessed in BALB/c mice following anterior chamber (AC) injection of C57BL/6 splenocytes. CFSE-based suppression assay was used to assess requirement for IL-17A by Tregs and was performed by incubating Tregs with CFSE-labeled CD4+ T cells from naïve mice boosted in vitro with anti-CD3 antibody. A local adoptive transfer (LAT) assay was used to measure suppression of allospecific DTH by Tregs isolated from BALB/c corneal allograft acceptors.
BALB/c mice rejected 50% of transplanted C57BL/6 corneas. Depletion of IL-17A increased the incidence of rejection to 90%; however, rejection was not due to exaggerated DTH. CFSE suppression assays showed that neutralization of IL-17A decreased the suppressive potential of allograft survivor Tregs by ~70%. LAT assays demonstrated that the Tregs suppressed the efferent phase of the alloimmune response and were able to suppress the anti-C57BL/6 DTH but not the anti-C3H DTH - suggesting antigen-specificity of the Tregs. IL-17A-depletion did not abrogate allospecific ACAID in BALB/c mice injected in the AC with C57BL/6 alloantigens.
IL-17A is necessary for the maintenance of ocular immune privilege. Depletion of IL-17A increases graft rejection but not as a result from loss of cross regulation of Th1 cells. Instead, IL-17A appears to promote graft survival by enhancing the suppressive potential of CD4+CD25+ Tregs. Although ACAID correlates with corneal allograft survival, induction of ACAID is IL-17A independent, suggesting that two distinct forms of CD4+CD25+ Tregs contribute to the success of corneal allografts.
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