Challenge by infectious agents requires an immediate and effective response by cells of the immune system to provide protection. By the very nature of this system , leukocyte populations need to be expanded to control the infection With regard to lymphocytes, foreign antigen recognition activates specific cells to proliferate resulting in clonal expansion. Once the challenge has been met, these populations contract, leaving specific memory cells. While many of the signals required to activate T lymphocytes have been characterized, how those signals result in changes in cell cycle are not well understood. Recently, in other eukaryotic systems there have been major advances in understanding the molecular mechanism by which cell cycle is controlled. Conserved in eukaryotic cells is a family of protein kinases, protein phosphatases and regulatory proteins termed cyclins, which interact to control the cell cycle. The enzymatic activity of p34cdc2 kinase is required for entry of cells into mitosis. p34cdc2 activity is regulated by its interaction with cyclins and dephosphorylation of critical amino acids near the amino terminus. The phosphatase responsible for dephosphorylating p34cdc2 is cdc25. Multiple isoforms of cdc25 are now known to exist; three have been characterized in humans and two have been reported in mouse. However, nothing is known about cdc25 expression in T lymphocytes; which isoforms are expressed; when in the cell cycle are they expressed; how their activity is regulated during the process of T cell activation ; and how they may function to regulate cell cycle.
The aims of this proposal are directed towards examining the role of cdc25 isoforms in regulating T cell proliferation. Mouse cdc25 isoforms expressed by T lymphocytes will be identified and characterized. The potential for cdc25 to act as a mitotic inducer in T cells will be examined. To determine the particular check point in the T cell cycle that cdc25 may regulate, the effects of in vivo modulation of cdc25 activity on cell cycle progression and induction of mitosis will be investigated. In addition, the potential role of cdc25 in programmed cell death (T cell apoptosis) will be analyzed. One possible model for apoptosis is the inappropriate initiation of mitotic events. Therefore, it is of interest to determine whether the induction of apoptosis results from the inappropriate induction of cdc25 activity. These studies have bearing on the control of lymphocyte repertoire expansion and contraction during an immune response and may be important in understanding the transformation of lymphocytes in lymphomas and leukemias.
| Woodford-Thomas, T; Thomas, M L (1993) The leukocyte common antigen, CD45 and other protein tyrosine phosphatases in hematopoietic cells. Semin Cell Biol 4:409-18 |
