To eliminate antigens that are recognized as nonself (foreign) the immune system uses many strategies, including antibodies and complement, activated macrophages, and T lymphocytes having cytotoxic activity. Our goal is to understand cytotoxic T lymphocytes (Tc cells), particularly their recognition of antigens in the restricted contest of autologous (self) histocompatibility (H) antigens and their activation of cytotoxic molecules and processes, which are triggered when these cytotoxic cells recognize target cells bearing the appropriate antigen (and H proteins). To understand antigen recognition we will compare the immunoglobullin (Ig)-like T cell receptor Alpah, Beta, and Gamma genes that are expressed in both mature Tc cells and in immature thymocytes, comparing especially V and V-J joining region sequences of receptors from cells of the three congenic BALB strains (BALB/c [H-2d], BALB.B [H-2b], and BALB.K [H-2k]). The comparison should reveal whether H antigens in the environment of developing T cells influences the V domains of the Alpha, Beta, and Gamma V chains and J that are expressed in mature Tc cells. The product and function of the Ig-like T cell Gamma Y gene are still enigmatic and special efforts will be made to identify the Gamma chain, focussing on the liklihood that it is a phosphorylated subunit of a membrane-associated, dimeric protein. Purified, soluble human H antigens will also be used to establish the intrinsic affinity of T cell receptors on cloned human Tc cell lines that are specific for these H antigens, some of which have a well-characterized 3-dimensional structure. T analyze some molecules involved in cytolysis of target cells, the properties of a novel esterase recentlly described in murine Tc cells will be analyzed and the gene encoding this enzyme will be studied to determine the extent of its homology, if any, to complement proteins. Finnally, heterobifunctional (""""""""duplex"""""""") antibodies will be studied to determine their effectiveness in targeting any selected cell for destruction by Tc cells, regardless of the latter's antigen-specificity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA042504-02
Application #
3479299
Study Section
(SRC)
Project Start
1986-06-01
Project End
1993-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Eisen, H N; Sykulev, Y; Tsomides, T J (1996) Antigen-specific T-cell receptors and their reactions with complexes formed by peptides with major histocompatibility complex proteins. Adv Protein Chem 49:1-56
Sykulev, Y; Cohen, R J; Eisen, H N (1995) The law of mass action governs antigen-stimulated cytolytic activity of CD8+ cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 92:11990-2
Kageyama, S; Tsomides, T J; Sykulev, Y et al. (1995) Variations in the number of peptide-MHC class I complexes required to activate cytotoxic T cell responses. J Immunol 154:567-76
Wu, M X; Tsomides, T J; Eisen, H N (1995) Tissue distribution of natural peptides derived from a ubiquitous dehydrogenase, including a novel liver-specific peptide that demonstrates the pronounced specificity of low affinity T cell reactions. J Immunol 154:4495-502
Sykulev, Y; Brunmark, A; Jackson, M et al. (1994) Kinetics and affinity of reactions between an antigen-specific T cell receptor and peptide-MHC complexes. Immunity 1:15-22
Dutz, J P; Tsomides, T J; Kageyama, S et al. (1994) A cytotoxic T lymphocyte clone can recognize the same naturally occurring self peptide in association with a self and nonself class I MHC protein. Mol Immunol 31:967-75
Tsomides, T J; Aldovini, A; Johnson, R P et al. (1994) Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J Exp Med 180:1283-93
Dutz, J P; Fruman, D A; Burakoff, S J et al. (1993) A role for calcineurin in degranulation of murine cytotoxic T lymphocytes. J Immunol 150:2591-8
Tsomides, T J; Eisen, H N (1993) Stoichiometric labeling of peptides by iodination on tyrosyl or histidyl residues. Anal Biochem 210:129-35
Su, M W; Walden, P R; Golan, D B et al. (1993) Cognate peptide-induced destruction of CD8+ cytotoxic T lymphocytes is due to fratricide. J Immunol 151:658-67

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