Role of IL-17A and Acaid in the Maintenance of Corneal Immune Privilege




Cunnusamy, Khrishen

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The human cornea, specifically the endothelial cell layer, has little to no regenerative potential. Accordingly, the eye has evolved multifactorial mechanisms that limit local immunogenic inflammation and trauma to the corneal endothelium. This local immune deviation is achieved through multiple anatomical, physiological, and immunoregulatory features intrinsic to the ocular environment that allow the cornea to enjoy an immune privileged status. Corneal immune privilege allows first time recipients of corneal allografts to enjoy a 90% success rate in the absence of systemic immunosuppressive drugs and without prior tissue typing. The myriad of immunoregulatory components that conspire to maintain the immune privilege of the cornea can be assigned to one of two extensively studied subsets. They include: (a) immunosuppressive molecules and membrane molecules present in the aqueous humor and on the surface of corneal cells layers, and (b) cell-mediated regulatory mechanisms such as anterior chamber-associated immune deviation (ACAID) that suppress systemic immune responses. This dissertation proposal investigates the role of a newly identified T cell subset, the Th17 CD4+ T cell lineage and its production of the cytokine, IL-17A in modulating corneal immune privilege and the outcome of keratoplasty. Previously, the Th17 T cell subset and its pro-inflammatory cytokine, IL-17A had been associated with the pathogenesis of several autoimmune diseases and had been implicated in cardiac, lung, and renal allograft rejections. Interestingly, in contrast to the classical paradigms that suggest that CD4+ T cells mediate graft rejection, the IL-17A produced by CD4+ T cells appears to be necessary for corneal allograft survival. My investigations led me to two distinct mechanisms via which IL-17A promotes corneal immune privilege. The results indicate that IL-17A is required for inhibiting the generation of an allospecific Th2 CD4+T cell subset that can independently exacerbate corneal allograft rejection. Simultaneously, IL-17A is also required for the functioning of CD4+CD25+ T regulatory cells (Tregs) that suppress alloimmune responses directed against the corneal transplant. Finally, by comparing and contrasting the cellular and cytokine requirements of corneal immune privilege and ACAID, these investigations unveil the independent mechanisms operating in the establishment of these respective phenomena. These findings redefine the role of IL-17A as a cytokine essential for the maintenance of corneal immune privilege and establish a new paradigm whereby interplay between IL-17A and CD4+CD25+ Tregs is necessary for survival of corneal allografts.

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