Manipulation of Follicular Helper T Cells in Immunity and Autoimmunity

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DESCRIPTION (provided by applicant): CD4 T cell help is crucial for B cell production of antibodies that occurs in germinal centers (GCs) of secondary lymphoid organs (SLOs), a site of immunoglobulin (Ig) affinity maturation and isotype switching. In GCs, T follicular helper (Tfh) cells provide B cells with survival and differentiation signals, including CD40 ligand (CD40), programmed death receptor-1 (PD-1), and IL-21, essential for B cell selection with maturation into memory B cells and long-lived antibody-secreting (plasma) cells. Tfh cells can be distinguished from other CD4 effector cells; e.g., the Th1, Th2, and Th17 subsets (among others), by their GC location and function as B cell helpers. Tfh cells are critical for B cell hel in both normal and autoimmune responses; yet, the development and function of these cells, compared to other CD4 T effector cell subsets, is less clear. To address this issue, we have devised an approach to selectively mark and/or delete these cells chronologically during normal and aberrant immune responses. To accomplish this goal, we will take advantage of our recent observation that ectodin, an inhibitor of bone morphogenetic proteins (BMPs), is selectively expressed by Tfh cells among other immune cells. Here we propose the development of an in vivo system to specifically target and manipulate Tfh cells using the ectodin promoter. We propose to make a tamoxifen-inducible-Cre mouse in which Cre, fused with the estrogen receptor ERT2, will be expressed downstream of the ectodin gene (Sostdc1); the targeting construct has already been made, sequence verified, purified, and micro-injected into embryonic stem cells. When crossed with the appropriate reporter strain (e.g., Rosa-26-YFP), deleter strain (R-DTA mouse) or with strain(s) that expresses a target gene flanked by two loxP sites, it will allow us to specifically track or ablate Tfh cells, or engender a Tfh- specific deletion of genes a desired time points during an immune or autoimmune response; the latter will be accomplished by crossing our inducible Cre mouse with appropriate lupus-prone strains. Currently there is no way to specifically target and analyze the role of Tfh cells in immune responses; thus, we believe our approach of creating an inducible, Tfh cell-specific Cre mouse will open up opportunities to study different aspects of Tfh biology. PUBLIC HEALTH RELEVANCE: Subset of T cells, follicular helper T cells, is necessary for helping B lymphocytes produce antibodies and autoantibodies in normal and autoimmune responses. Much remains to be learned about the biology of the former, including the requirements for their maturation and function, and how to interrupt their collaboration with B cells as a potential therapy for autoimmune diseases. The results of the proposed studies should help address these issues, and advance knowledge of how autoimmune responses develop in humans.