B Cell Help for Alloreactive T Cell Memory

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Immunologic memory is a hallmark of the adaptive immune response. Memory lymphocytes are long lived, respond vigorously upon re-exposure to antigen, and mediate rapid immunologic protection against infections. On the other hand, memory responses to donor alloantigens jeopardize the survival of life-saving organ transplants. Despite immunosuppression, many patients develop donor-reactive memory T cells after transplantation that lead to acute allograft rejection or chronic graft loss. Thus, understanding the biology of memory T cells is essential for developing better anti-rejection therapies. Allograft rejection is a T cell dependent process, though B cells contribute to both acute and chronic rejection. Traditionally, B lymphocytes have been viewed as effector cells that are dependent on T cell help to undergo proliferation and differentiation. Our preliminary data in mouse transplantation models, however, indicate that B cells have an important 'helper' function in T cell responses, specifically that they promote T cell differentiation into memory lymphocytes. Importantly, current clinical immunosuppression regimens inhibit na[unreadable]ve but neither memory T cell nor B cell responses. The goal of this grant application, therefore, is to investigate how B cells promote generation of alloreactive memory T cells. The proposed experiments will investigate if B cells function as antigen presenting cells and if B cells provide co-stimulation to promote alloreactive T cell differentiation to memory. Mixed bone marrow chimera will be created where-in B cell antigen presenting function or B cell co-stimulatory function is disrupted and test whether such B cells now fail to promote generation of alloreactive memory T cells. The proposed work constitutes a new and independent direction of research for the applicant and will provide the essential groundwork for a subsequent R01-type application. B cells and memory T cells contribute to both acute and chronic allograft rejection. We will investigate how B cells promote generation of donor-reactive memory T cells. Understanding these mechanisms will shed insight into how and when to target B cell responses after transplantation to interrupt ongoing memory generation and impact long-term allograft survival. [unreadable] [unreadable] [unreadable]