Initiation and Regulation of Type 2 Immunity and Inflammation at Mucosal Sites

Identifying the cellular and molecular requirements for initiating and regulating type 2 immunity and inflammation is essential for the development of new vaccines against helminth parasites and treatments for atopic diseases. CD11c+ dendritic cells (DCs) are critical antigen-presenting cells (APCs) capable of priming and promoting the differentiation of naïve CD4+ T cells. However, the role of DCs in the initiation of Th2 cell differentiation following exposure to helminth parasites and allergens remains unclear. In Chapter 2, we examine the cellular requisites for initiating Th2 cytokine-dependent immunity and inflammation in the gastrointestinal tract utilizing infection with the helminth Trichuris muris. By genetic restriction of MHC class II expression to CD11c+ DCs we demonstrate that, in contrast to Th1-cytokine-mediated immunity, antigen presentation by CD11c+ cells is insufficient to generate protective type 2 immune responses in vivo, suggesting additional non-DC APC interactions may be required for Th2 cell differentiation. In Chapter 3 we identify basophils as a cell population that expanded following exposure to Trichuris and expressed both IL-4 message and MHC class II. Depletion of basophils resulted in impaired immunity to Trichuris and purified basophils promoted CD4+ T cell proliferation and Th2 cell differentiation in vitro and in vivo. Chapter 4 explores the regulation of type 2 immune responses in the intestine and lung by IL-31, a cytokine produced predominantly by Th2 cells that signals through a heterodimeric receptor composed of OSMR and IL-31Rα. IL-31Rα deficient mice exhibited enhanced Th2 cytokine production, elevated IgE levels and increased type 2 inflammation following both Trichuris infection and in an acute model of airway inflammation after exposure to Schistosoma mansoni eggs. Taken together, the results presented in this thesis demonstrate that DCs are not sufficient to promote Th2 cell responses in vivo during Trichuris infection and are the first report of an APC function for basophils in promoting Th2 cell responses. In addition, they identify a novel regulatory role for IL-31R in limiting the magnitude of Th2 cytokine-dependent immunity and inflammation