T cell differentiation occurs under the influence of the thymic micro- environment within which bone marrow derived progenitor cells proliferate and differentiate to generate immunocompetent T lymphocytes. The main objective of this proposal is to study regulation of expression of the CD3- gamma, delta, and epsilon genes which set the stage for intrathymic differentiation through their control of cell surface expression of the T Cell Receptor/CD3 Complex (TCRalphabeta/CD3gammadeltaepsilonzeta2 or TCRgammadelta/CD3gammadeltaepsilonzeta2). The first major function of CD3- gamma, -delta and -epsilon lies in their involvement in transduction of the signal caused by TCR/antigen/MHC interactions. But, despite rapid progress in the molecular anatomy of the TCR/CD3 Complex, much needs to be learned about the biochemical mechanisms of signal transduction. The other principal function of the CD3 proteins is in regulation of cell surface assembly of the TCR/CD3 Complex. In the mature, functionally competent T lymphocyte the multi-chain TCR/CD3 Complex is constructed around a protein core consisting of CD3-gamma, delta, epsilon. T Cell Receptor alpha and beta (or TCR gamma and delta) are subsequently added to the CD3-gamma, -delta, -epsilon core thus facilitating the heterodimer formation and disulfide linkage. Finally, CD3-zeta is added to the pentameric alpha,beta,gamma,delta,epsilon subcomplex. The CD3-delta, -delta and -epsilon are the only known genes that are expressed in all cells of T lineage, but not in any other cell type. Our interest in the CD3 -gamma, -delta, epsilon genes cluster lies therefore not only in the important functions of their gene products, but also in the unique developmental regulation of their expression. It is plausable that the CD3 genes are not only critical markers for thymic development, but are also sine qua non for commitment to the T lineage.
The SPECIFIC AIMS of this proposal are to: 1. Study T cell specific transcriptional regulation of the CD3-delta gene. 2. Investigate the molecular mechanisms that govern T cell specific expression of the CD3-epsilon gene. 3. Characterize transcriptional elements involved in expression of the CD3-gamma gene in T cells. 4. Examine the coordinate regulation of the CD3-gamma, -delta, -epsilon genes during intrathymic differentiation.
| Porcelli, Steven; Brenner, Michael B; Greenstein, Julia L et al. (2010) Recognition of Cluster of Differentiation 1 Antigens by Human CD4-CD8- CytolyticT Lymphocyte. Nature. 1989. 341: 447-450. 1989. J Immunol 184:3306-9 |
