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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032609-02
Application #
3147744
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030