Generation & Regulation of Tfh13 cells that drive Pathogenic IgE in Allergy

Abstract: Allergies to food and environmental antigens have steeply grown to epidemic proportions. One key determinant of IgE-mediated clinical symptoms is the high-affinity of the IgE antibody for a given allergen which we will refer to as “pathogenic IgE”. A life-threatening complication associated with pathogenic IgE mediated allergic reaction is anaphylaxis, which can lead to the death of otherwise healthy individuals, including children. Follicular helper T cells (Tfh), but not Th2 effector cells, are primarily responsible for directing the affinity, longevity and isotype of antibody produced by B cells, including IgE. The nature of the Tfh cells that drive high-affinity, pathogenic IgE to allergens was unclear. We recently discovered that allergens drive the differentiation of a novel Tfh cell subset namely Tfh13 cells in addition to canonical Tfh2 cells. Tfh13 cells co-produce IL-4 and IL-13, express low levels of IL-21 and are absolutely required for allergen-specific pathogenic IgE production. Importantly, Tfh13 cells are found in patients with food or respiratory allergies but not in healthy individuals. Despite the importance of Tfh13 cells in allergies, currently little is known about how Tfh13 cells differentiate during allergic sensitization. While Tfh2 cells are elicited in response to vaccinations, viral infections, and almost all type 2 responses, Tfh13 cells are specifically generated in allergic disease states. This highlights the existence of vital signals during sensitization that foster Tfh13 cell differentiation, with the possibility of conflicting signals in non-allergic contexts. The goal of our proposal is to fill these gaps in knowledge and thereby elucidate pathways that lead to Tfh13 cell differentiation. The overarching hypothesis that our proposal aims to test is that Tfh2 cells and Tfh13 cells have distinct immunological requirements for their differentiation. We have developed tools including cell specific knockout mice to 1) determine the role of non-conventional antigen presenting cells in promoting Tfh13 cell differentiation to allergens and 2) elucidate the how the balance of type II cytokines and their inhibitory signals determine the Tfh2 versus Tfh13 cell fate decision. The broad impact of our studies could be substantial, enabling the elucidation of the cell extrinsic and intrinsic pathways of Tfh13 cell differentiation that could be leveraged to curtail allergic disease.