Suppression of immunologic reactivity is one of the major mechanisms by which tumors are thought to escape host defense mechanisms. However, how tumors suppress immune responses is not clear. Recent studies have shown that for the induction of T cell responses two signals are required from the antigen presenting cell, one that is antigen specific and is provided by the antigen-MHC complex and a second non-specific costimulatory signal which is provided by the B7 molecules. In the absence of a costimulatory signal, T cells are inactivated or anergized. The B7 family consists of two molecules (B7.1 and B7.2) both of which can interact with two counter-receptors CD28 and CTLA4 on T cells. Engagement of B7 molecules with CD28 induces a positive signal leading to T cell proliferation whereas interaction with CMA4 induces a negative signal and turns off the T cell response. Expression of B7.1 and B7.2 in tumor cells has led to the generation of immunocompetent tumor cells that induce anti-tumor immunity and tumor regression. The applicant expressed either B7.1 or B7.2 molecules in a T lymphoma cell line, EL-4. While EL4-B7.1 cells induced T cell costimulation and tumor regression, surprisingly the ELA-B7.2 or EL-4-B7.1 plus B7.2 double transfectants did not induce tumor regression but progressively grew in syngeneic mice. To further understand the biochemical and molecular basis for this surprising result, the applicant proposes the following specific aims: He will 1) determine whether lack of induction of anti-tumor immunity by B7.2 expressed on T cells is because of quantitative differences in the expression of B7.2 on the surface of T cells. Furthermore he will test whether B7.2 affects expression/upregulation of other accessory molecules critical in the induction of T cell response; 2) determine whether lack of induction of antitumor immunity is because B7-2 expressed on T cells is qualitatively different. He will test whether B7.2 expressed on T cells is altered by post-translational modifications (glycosylation) or by splicing or introduction of mutations, which affects its ability to bind CD28. Since different isoforms of B7.2 have been isolated he will also test the effect of expression of other isoforms of B7.2 on the induction of anti-tumor immunity 3) Determine the nature and type (including CTL activity, cytokine profile and function upon adoptive transfer) of T cell response induced against B7.2 and B7.1 plus B7.2 transfected EL-4 cells and test the mechanism by which they inhibit anti-tumor immunity.
| Baroja, Miren L; Vijayakrishnan, Lalitha; Bettelli, Estelle et al. (2002) Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J Immunol 168:5070-8 |
| Mandelbrot, D A; Oosterwegel, M A; Shimizu, K et al. (2001) B7-dependent T-cell costimulation in mice lacking CD28 and CTLA4. J Clin Invest 107:881-7 |
