Role of Intestinal Parasites on Regulating Immune Responses to Gut Antigens

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PROJECT SUMMARY/ABSTRACT Gastrointestinal parasitic infection is a widespread global health problem and can be a cause of significant morbidity. Nevertheless, there is limited information on how T cells respond to these parasites. In some cases, despite a robust T cell effector response to the parasite, tolerance to food antigens is maintained or enhanced. This has led to the notion that chronic parasitic infection could explain in part the hygiene hypothesis, which states that elimination of colonization or reduction of recurrent infections due to sanitation and pest control increases the risk of allergic and autoimmune diseases. We aim to understand how intestinal parasites induce effector T cell responses to parasitic antigens, and yet facilitate tolerance to food antigens present in the intestine. We will study two parasites that induce opposite T cell effector responses in mice. We will use a newly identified strain of Cryptosporidium tyzzeri, a commensal protozoan that induces a Th1 response, and H. polygyrus, a helminth that induces a Th2 response. The rationale for using parasites which elicit disparate T helper responses is to uncover potentially convergent mechanisms that may underly prevention of immunopathology during anti-parasitic responses and maintenance of tolerance to innocuous food antigens. In each infection, we will use TCR repertoire analysis to identify parasite-specific TCRs expressed by CD4+ T cells. This approach will allow us, for the first time, to precisely track the fate of such parasite-reactive T cells during these infections as they differentiate from naïve T cells to effectors or regulatory subsets. Given the central role of the transcription factor Bhlhe40 in regulating effector function and IL-10 production, we will also test its role in parasite-specific T cell fates and the development of a Tr1 phenotype which may provide immune tolerance to these parasites. In Aim 1 we will characterize the anti-parasite T cell response to H. polygyrus. In Aim 2, we will evaluate the mechanisms that regulate immune tolerance to Cryptosporidium. In Aim 3, we will determine how infection with these parasites impacts on the tolerogenic T cell response to food antigens and on the induction of food allergy. Overall, these studies will provide novel and important insights into how parasitic infections drive effector T cell responses to parasite antigens while simultaneously promoting tolerogenic or pathogenic responses to food antigens.