The thymic transcription factor AIRE prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1 specific T cells without affecting thymic numbers of regulatory T cells. Aire deficient mice displayed elevated T cell immune responses that were associated with suppression of melanoma outgrowth. Further, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wildtype host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma, and how manipulating TRP-1 specific T cell negative selection may offer a logical strategy to enhance immune rejection of melanoma.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) results from autoimmune destruction of the peripheral nervous system (PNS) and is a component of the multi-organ autoimmunity syndrome which results from Autoimmune Regulator (Aire) gene mutations in humans. In parallel, PNS autoimmunity resembling CIDP develops spontaneously in NOD mice with a partial loss of Aire function (NOD.AireGW/+ mice), and is a T cell-mediated disease. In this study, we analyze how key aspects of T cell activation and function modulate disease development in Aire-deficient mice. We show here that genetic ablation of the Th1 cytokine IFNγ completely prevents clinical and electrophysiological evidence of neuropathy in NOD.AireGW/+ mice. IFNγ deficiency is associated with absence of immune infiltration and decreased expression of the T cell chemoattractant IP-10 in sciatic nerves. Thus, IFNγ is absolutely required for the development of autoimmune peripheral neuropathy in NOD.AireGW/+ mice. Because IFNγ secretion is enhanced by B7-CD28 costimulation of T cells, we sought to determine the effects of these costimulatory molecules on neuropathy development. Surprisingly, B7-2 deficiency accelerated neuropathy development in NOD.AireGW/+ mice, and antibody blockade of both B7-1 and B7-2 resulted in fulminant, early-onset neuropathy. Thus, in contrast to IFNγ, B7-2 alone and B7-1/B7-2 in combination function to ameliorate neuropathy development in NOD.AireGW/+ mice. Together, these findings reveal distinct and opposing effects of T cell costimulatory pathways and IFNγ production on the pathogenesis of autoimmune peripheral neuropathy.

No abstract