Costimulatory B7 molecules (B7-1 or CD80; and B7-2 or CD86) are known to bind to T cell costimulatory receptors CD28 and CTLA4. Engagement of CD28 is know to transduce signals in T cells that play a critical role in T cell activation; however, little is known of the ability of B7 molecules to themselves act as signal transducing molecules. The effect of B7-1 and B7-2 crosslinking was assessed in the B cell lymphoma BAL.17. Initial studies demonstrated that B7 crosslinking induces AP-1 components including c-fos and c-jun, as demonstrated by gel retardation and ?super-shift? assays. These findings indicate that B7 engagement by counter-receptors such as CD28 or CTLA4 may lead to bidirectional effects, functioning to transduce signals in B7- expressing cells such as B lymphocytes, in addition to signaling CD28/CTLA4 positive T cells.The role of CD28/B7 interactions has been analyzed in host responses to antigenic tumor. EL4 tumor cells grew progressively in syngeneic B6 mice. However, transfection of EL4 with B7-1 or B7-2 costimulatory ligands resulted in tumor rejection and the induction of tumor-specific immunity. Tumor rejection under these conditions was dependent upon the presence of the B7 receptor CD28 as demonstrated using CD28-deficient B6 mice for tumor challenge. These results demonstrated for the first time the requirement for CD28 as a B7 receptor in tumor rejection. The role of B7 cytoplasmic domains in tumor rejection was tested by transfection of EL4 cells with cytoplasmic deletion mutants of B7-1 and B7-2, and it was found that tumor rejection was not influenced by the presence or absence of B7 cytoplasmic domains. These results indicate that CD28 interaction with extracellular B7-1 or B7-2 domains can mediate costimulatory function for syngeneic tumor rejection. The effect of costimulus in T cell development and repertoire selection was studied using transgenic mice that over-express B7-1(CD80) or B7-2 (CD86). Initial data indicate that expression of costimulatory B7 ligands has a substantial effect on CD4 and CD8 differentiation. Further studies are in progress to assess the mechanism of this effect. - B lymphocytes, Cell signaling, immune response, receptors, T lymphocytes,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009281-13
Application #
6289248
Study Section
Special Emphasis Panel (EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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