The goal of this project is to analyze the factors that control the differentiation of naive CD4+ T-cells into effector subsets with restricted cytokine profiles, and the cellular and biochemical mechanisms of this differentiation process. The proposed studies are based on the hypothesis that CD4+ T-cell differentiation may be divided into an induction phase, in which exogenous cytokines regulate cytokine gene transcription in antigen-stimulated T-cells, and an amplification phase, in which antigen-presenting cells (APCs) and other cytokines expand or suppress differentiation T-cells. Antigen itself may act in both phases, by regulating the pattern of cytokine production and by inducing selective growth or tolerance of particular subsets. Based on this hypothesis, the application proposes the following specific aims to address the major unresolved questions about CD4+ T-cell differentiation.
Specific Aim 1 proposes to study the differentiation of T lymphocytes in vivo. The factors that regulate CD4+ T-cell differentiation in vivo will be studied in normal and T-cell receptor (TCR) transgenic mice immunized in ways that give rise to Th1- or Th2- dominant responses. The roles of cytokines will be examined by immunohistochemistry, and by regulating T-cell differentiation with recombinant cytokines and specific antagonists. The roles of APCs will be studied in B-cell-deficient mice, and of costimulators in mice treated with soluble CTLA4. The relationship between antigen-induced tolerance and selective differentiation to one subset will be examined.
Specific Aim 2 proposes to study the mechanisms of T-cell differentiation in vitro. The effects of exogenous cytokines, APCs, costimulators, and antigens on cytokine gene transcription in antigen or SEB-stimulated T- cells will be examined. The mechanisms of transcriptional control of cytokine genes will be studied, with special emphasis on analysis of transcription factors. Model antigens and peptide analogs will be used to selectively regulate expansion or induce tolerance in differentiating Th1- or Th2-like cells. Thus, this application uses a combination of established and novel in vitro and in vivo model systems to study fundamental questions about T-cell differentiation and the physiologic functions of selected cytokines. Elucidating the mechanisms of CD4+ T- cell differentiation is the key to designing rational approaches for selectively augmenting or suppressing particular T-cell subsets in infectious, allergic, and autoimmune diseases.
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