gammadelta+ T cells are found in all vertebrates examined. They reside in the thymus, secondary lymphoid organs, and epithelial layers, and display some functions common to alphabeta T cells, including cytolytic activity and lymphokine production. While their physiological functions remain to be defined, it is highly likely gammadelta cells play an important role(s) in immunity. An understanding of these roles requires considerable further information concerning their specificity and function. In addition the gammadelta receptor system can serve as a relatively simple system to evaluate the regulation of antigen receptor gene rearrangement and expression in general. Two general issues concerning the immunobiology of gammadelta cells are addressed in this proposal. The first concerns the important question whether MHC molecules play a role in restricting recognition by gammadelta cells or in the maturation of gammadelta cells in ontogeny. To explore this issue we propose to analyze gammadelta cell differentiation, function and recognition in unique mutant mice that lack beta2-microglobulin expression, and hence fail to functionally express class 1 MHC molecules. The second issue addressed pertains to the highly ordered ontogenic regulation of the intrathymic production of subtypes of gammadelta cells that express different Vgamma/Vdelta genes, are destined for distinct peripheral localization, and presumably recognize distinct sets of physiological ligands. The existing data suggest that molecular mechanisms target specific sets of V genes for rearrangement at different stages in ontogeny. We propose to test this model directly, and define relevant target sequences, with the use of mice transgenic for defined rearrangement substrates. In addition, further analysis of gamma enhancer and negative regulatory elements is to be addressed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI031650-01
Application #
3146698
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Whang, Michael I; Guerra, Nadia; Raulet, David H (2009) Costimulation of dendritic epidermal gammadelta T cells by a new NKG2D ligand expressed specifically in the skin. J Immunol 182:4557-64
Uche, Uzodinma N; Huber, Christopher R; Raulet, David H et al. (2009) Recombination signal sequence-associated restriction on TCRdelta gene rearrangement affects the development of tissue-specific gammadelta T cells. J Immunol 183:4931-9
Xiong, Na; Zhang, Li; Kang, Chulho et al. (2008) Gene placement and competition control T cell receptor gamma variable region gene rearrangement. J Exp Med 205:929-38
Xiong, Na; Kang, Chuhlo; Raulet, David H (2004) Positive selection of dendritic epidermal gammadelta T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21:121-31
Xiong, Na; Kang, Chulho; Raulet, David H (2002) Redundant and unique roles of two enhancer elements in the TCRgamma locus in gene regulation and gammadelta T cell development. Immunity 16:453-63
Baker, J E; Kang, J; Xiong, N et al. (1999) A novel element upstream of the Vgamma2 gene in the murine T cell receptor gamma locus cooperates with the 3' enhancer to act as a locus control region. J Exp Med 190:669-79
Kang, J; Coles, M; Cado, D et al. (1998) The developmental fate of T cells is critically influenced by TCRgammadelta expression. Immunity 8:427-38
Baker, J E; Cado, D; Raulet, D H (1998) Developmentally programmed rearrangement of T cell receptor Vgamma genes is controlled by sequences immediately upstream of the Vgamma genes. Immunity 9:159-68
Zerrahn, J; Held, W; Raulet, D H (1997) The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88:627-36
Kang, J; Raulet, D H (1997) Events that regulate differentiation of alpha beta TCR+ and gamma delta TCR+ T cells from a common precursor. Semin Immunol 9:171-9

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