Research Project
8282924
DESCRIPTION (provided by applicant): Soil transmitted helminth parasites are one of the most commonly acquired infections and world wide according to the WHO. These infections elicit robust CD4+ T helper and B cell responses. The CD4+ T helper cells are highly Th2 polarized and produce IL-4 upon restimulation. The accompanying B cell response is characterized by high serum concentrations of the type 2 immunoglobulins IgG1 and IgE. Experimental infection of mice with the murine helminth parasite Heligmosomoides polygyrus induces these prototypic responses and is an exceptionally powerful model to study fundamental principles of Th2 development, IL-4 production and type 2 B cell responses in vivo. The function of Th2 polarized CD4+ T cells to provide unidirectional B cell help is widely accepted. However, the possibility that Th2 differentiation and type 2 B cell response develop in interdependence has received little attention. Our preliminary data provide two key findings. First, IL-4R1-/- mice initiate the development of Th2 cells early on, but in contrast to wt mice, their expansion and maturation is aborted. Strikingly, the defective Th2 response is accompanied by the almost complete absence of expansion and maturation of the B cell response. Moreover, these mice are not protected from a recall infection with H. polygyrus. Secondly, like IL-4R1-/- mice, B cell-deficient mice also fail to fully mature an initiated Th2 response and are also not protected from a recall infection. Collectively our preliminary data have established that early Th2 cell development is initiated independently of B cells and IL-4R1- mediated signals but fails to progress and mature. It is our central hypothesis that Th2 cells are required for the expansion and maturation of a B cell response which is in turn critical for the full expansion and maturation of the initiated Th2 response. We hypothesize that CD4+ T cell-derived IL-4 and antigen presentation by B cells are critical for the interdependence between T cells and B cells in Th2 cell differentiation. We will test this hypothesis by using a unique set of IL-4 reporter mice and mixed bone marrow chimeric mice to dissect the B cell response in the absence of IL-4R1-mediated signals and the Th2 response generated in the absence of B cells. We will test the functional potential of Th2 cells generated in the absence of B cells in vitro and upon adoptive transfer into wt hosts. Finally we will test whether B cells are also critical during the recall function of Th2 cells primed in a wild-type environment. We are convinced that our studies will advance our understanding of Th2 development in interdependence to the associated B cell response. These fundamental insights will be relevant for Th2 responses in the context of infection and vaccination as well as atopic, asthmatic, and allergic disorders. Project Narrative Th2 cell-associated diseases afflict billions of people world wide and millions of individuals in the US alone. Understanding the fundamental mechanisms of Th2 cell differentiation is a prerequisite for the development of more efficient vaccines and the amelioration of asthmatic, allergic, and atopic disorders.
