Abstract

The objective of this research proposal is to further our understanding of T cell development and T cell function in health and disease. To this end we will use methods of molecular biology (cloning, polymerase chain reaction aided analytical methods, chromosome walking, site directed mutagenesis, gene transfection for transient and stable expression, gel retardation assays, construction of transgenic mice and of mutant mice using the ES cell homologous integration technique) as well as cell and thymus organ culture techniques, cell fusion techniques, flow cytometry, immunohistology and various in vivo assay for T cell functions (skin grafting, ear assay for delayed type hypersensitivity). We will study the molecular mechanism of the initial steps of alpha/beta and gamma/delta T cell differentiation, gamma/delta TCR repertoire generation, positive and negative selection alpha/beta and gamma/delta T cells in the thymus and the homing of gamma/delta T cell subsets to different epithelia. We will analyse TL and CD1 genes and the putative role of their products as antigen presenting proteins for gamma/delta T cells and investigate the molecular details and the putative biological significance of heat shock protein recognition by gamma/delta T cells. A major effort will be made to elucidate the in vivo function of gamma/delta T cells in lymphocyte development, in various immune responses (antibody responses, DTH responses, graft rejection) as well as in infectious diseases, auto immune diseases and tumor immunity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA053874-02
Application #
3479799
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1991-04-01
Project End
1998-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139

  Publications

Ohkanda, J; Lockman, J W; Yokoyama, K et al. (2001) Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity. Bioorg Med Chem Lett 11:761-4
Levelt, C N; de Jong, Y P; Mizoguchi, E et al. (1999) High- and low-affinity single-peptide/MHC ligands have distinct effects on the development of mucosal CD8alphaalpha and CD8alphabeta T lymphocytes. Proc Natl Acad Sci U S A 96:5628-33
Van de Keere, F; Tonegawa, S (1998) CD4(+) T cells prevent spontaneous experimental autoimmune encephalomyelitis in anti-myelin basic protein T cell receptor transgenic mice. J Exp Med 188:1875-82
Delaney, J R; Sykulev, Y; Eisen, H N et al. (1998) Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection. Proc Natl Acad Sci U S A 95:5235-40
Levelt, C N; Mizoguchi, E; Huang, X et al. (1998) Inhibition of intrathymic T cell development by expression of a transgenic antagonist peptide. Proc Natl Acad Sci U S A 95:14349-54
Marusic, S; Tonegawa, S (1997) Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide. J Exp Med 186:507-15
Lafaille, J J; Keere, F V; Hsu, A L et al. (1997) Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J Exp Med 186:307-12
Gerber, D J; Pereira, P; Huang, S Y et al. (1996) Expression of alpha v and beta 3 integrin chains on murine lymphocytes. Proc Natl Acad Sci U S A 93:14698-703
Bachmann, M F; Oxenius, A; Pircher, H et al. (1995) TAP1-independent loading of class I molecules by exogenous viral proteins. Eur J Immunol 25:1739-43
Hombach, J; Pircher, H; Tonegawa, S et al. (1995) Strictly transporter of antigen presentation (TAP)-dependent presentation of an immunodominant cytotoxic T lymphocyte epitope in the signal sequence of a virus protein. J Exp Med 182:1615-9

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