More than 20% of the human genome encodes proteins that are devoted to cellular signalling. Signal networks that involve the signal molecule cyclic AMP (cAMP) are involved in diseases such as cancer, cardiovascular disease, type II diabetes, obesity, HIV and asthma. Cyclic AMP acts as an acute inhibitor of T cell activation that prevents T cell proliferation and cytokine production. We have previously mapped a novel regulatory pathway in T cell lipid rafts involving cAMP- PKA type I and C-terminal Src kin ase (Csk) that modulate immune function in T effector cells. One of the main objectives of the present proposal is to investigate whether cAMP signalling is involved in the Treg induced immune suppression of T effector cells during anti-neoplastic immune responses.
By combining complementary expertise held by our group and collaborators both nationally and internationally, we will co-ordinate an effort to understand a key question in clinical immunology and cancer research. Based upon proven expertise, a particular approach will be to understand how regulatory T cells suppress anti-tumor immune function. Our unpublished preliminary data suggest that the Treg-mediated immune suppression of anti-tumor activity involves activation of the cAMP signalling pat hway in engaged T cells and through this mechansim inhibits the immune response. Specific objectives include: 1) Identification of the molecular mechanism employed by adaptive regulatory T cells in inhibition of surrounding T effector cells. 2) Identifica tion and characterization of regulatory T cells in relation to colon cancer and other neoplasms. 3) In vitro evaluation of the suppressive function of regulatory T cells on specific anti-tumor immune activity. 4) Target the molecular inhibitory function e mployed by regulatory T cells in order to enhance the anti-neoplastic immune function in vitro. 5) Develop clinically useful strategies for improving the immune function against malignant tumors.