Assessing food-specific tolerogenic CD4+ T cells in protection from food allergy - PROJECT SUMMARY/ABSTRACT Food allergy is an increasingly common global medical issue with no cure and limited treatment options. Food allergies are often lifelong and a leading cause of severe and/or fatal anaphylaxis, a rapid-onset systemic allergic reaction. While type 2 immune responses and production of food-specific IgE and IgG antibodies are implicated in food allergy, the immunologic mechanisms that regulate these processes are poorly understood. Human clinical studies suggest that early oral exposure to food antigens decreases the risk of developing food allergy while environmental exposures through non-oral routes, such as the skin or airways, increase the risk. Thus, route of allergen exposure is considered a key factor determining clinical outcomes in food allergy. However, major knowledge gaps remain as to whether and how oral consumption of foods provide systemic protection from allergic sensitization and clinical manifestations of food allergy. Thus, the overall goal of this project is to better understand the mechanisms by which oral exposure to food antigen protects from development of food allergy. In a mouse model of food allergy, we have identified a critical role for T follicular helper (Tfh) cells in promoting antigen-specific IgE production following intranasal (i.n.) or epicutaneous (e.c.) antigen exposure (considered natural routes of sensitization in humans). Upon systemic challenge with antigen, sensitized mice showed clinical symptoms of acute systemic anaphylaxis. Further, we found that oral consumption of antigen prior to i.n. or e.c. exposure protected mice from developing food allergy. Interestingly, the protection was not associated with expansion of conventional Foxp3-positive (Foxp3+) CD4+ T regulatory (Treg) cells but rather the emergence of population(s) of CD4+ T cells expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in draining lymph nodes. Thus, the objective of this proposal is to leverage these models and address key questions regarding the origins, phenotypes, and functions of these protective CTLA-4+ CD4+ T cells. Specifically, we hypothesize that oral exposure to antigen induces tolerogenic non-canonical antigen-specific CD4+ T cells that prevent systemic allergic sensitization to the same antigen and protect from development of IgE antibody and anaphylaxis. Aim 1 will employ a mouse model of food allergy and oral tolerance to characterize antigen-specific tolerogenic CD4+ T cells generated by oral exposure to food antigens through use of immunologic and genetic tools. In Aim 2, we will investigate the physiologic functions of these T cells in preventing type 2 immune responses and food allergy leveraging in vivo antibody blocking and adoptive transfer models. Overall, these findings will identify mechanisms involved in food allergy development and prevention and facilitate more effective and safer strategies to prevent and treat the disease in humans. Performance of these projects will help to me to advance my experience and expertise with in vitro and in vivo immunological techniques and to learn cutting-edge immunologic and genetic methods.
