This proposal concerns the activation and function of T cells that are growth-stimulated by transforming growth factor beta (TGF-beta), typically a potent inhibitor of immune responses. TGF-beta is a peptide with diverse regulatory functions in a wide array of tissue systems. In the immune system TGF-beta has been recognized as an inhibitor of lymphocyte proliferation and of multiple effector functions. However, recent studies from this laboratory indicate that TGF-beta has the capacity to costimulate, as well as inhibit T cell growth under appropriate conditions of T cell receptor activation. These studies suggest that TGF-beta-induced proliferation occurs independently of typical T cell growth factors and causes rapid evolution of a mature or memory population phenotype. Further, naive T cells or a subset thereof appear to proliferate in response to TGF-beta while mature T cells are suppressed. The proposed studies will address the cell subsets, the activating stimuli and the immunologic functions of TGF-beta expanded T cells. T cell subpopulations that proliferate in response to TGF-beta will be identified by flow cytometric sorting based on differentiation and functional subset markers. Characterization of co-activating stimuli will include analyses of T cell alpha/beta receptor ligands and T cell receptor activation mimics. Lymphokines that are produced by TGF-beta-stimulated T cells and that contribute to TGF-beta-dependent T cell proliferation will be characterized for production and receptor display. Differential expression of distinct TGF-beta receptor types will be assessed. The expression and role of adhesion/activation molecules that are rapidly induced on naive cells by TGF-beta will be investigated for their contribution to growth stimulation. The functional capacity of TGF-beta expanded T cells will be examined by assessment of requirements for sustained growth and possible development of TGF-beta dependent lines, lymphokine production, and cytolytic and regulatory functions. Application of these findings may provide new insights to issues of T cell selection and anergy, as well as to processes of immunodeficiency and autoimmune disease.
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| Sligh Jr, J E; Ballantyne, C M; Rich, S S et al. (1993) Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A 90:8529-33 |
