The control of allergic immune responses by follicular regulatory T cells

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ABSTRACT Allergic disease and asthma remain major health problems in the United States that impact quality of life and result in billions of dollars spent annually on healthcare and lost productivity . Immunoglobulin E (IgE) is the primary mediator of the immediate hypersensitivity involved in allergic disease . Following sensitization of the immune system to helminthic parasites or allergens, the ensuing type 2 response leads to IL-4 production from T cells and class switching to IgE in B cells. Systemic IgE binds to mast cells and basophils via the FcεRI, and upon subsequent challenge with antigen, crosslinked IgE-bound receptors stimulate release of anaphylactic mediators and cytokines. CD4 T cells are critical in the development of the IgE response. Yet, how T cells regulate IgE class switching, production and affinity maturation is not completely understood. The dogma for most of the past two decades was that T helper type 2 (TH2) cells promoted the IgE response through their ability to secrete IL-4. More recently, the identification of T follicular helper ( TFH) cells added an additional layer of complexity to the IgE response. TFH cells localize to, and control the development of, germinal centers (GCs), the major location of B cell activation, differentiation, class switching, and antibody affinity maturation. In some mouse models of allergic responses, TFH cells are absolutely required for IgE switching, and are also essential for the formation of TH2 effector cells. GC B cell responses are also regulated by T follicular regulatory (TFR) cells, which express both Bcl6 and Foxp3 and localize to the GC. In several mouse models, TFR cells have a range of effects on antibody production, from enhancing Ig affinity to suppressing overall Ig production to suppressing IgA switching. TFR cells can also suppress cytokine production by TFH cells. Recently, we have found that TFR cells can suppress the production of IgE in mice. However, the mechanism of IgE control by TFR cells is not understood, and the overall extent to which TFR cells control allergic immune responses has not been characterized. The goal of this application is to define the contributions of TFR cells to IgE production, IgE affinity maturation and TH2 effector T cell responses, as part of the larger goal of gaining new insights into the control of allergic diseases by T cells. We will analyze these aspects of allergic disease using two conditional mutant mouse models we have developed, and models for both airway and gastrointestinial (GI) allergic inflammation. Our overall hypothesis is that TFR cells repress TH2 and IgE responses by regulating TFH cells, but that TFR cells also enhance IgE affinity maturation.