The goals of this research program are to develop a comprehensive understanding of the roles of colony stimulating factor and suppressive cytokine producing T lymphocytes in hematopoiesis, and to provide the tools for regulating hematopoietic engraftment following bone marrow transplantation. Since the beginning of this program funded under the previous R01, the major findings have been: 1)T lymphocytes in recovering bone marrow transplant recipients fail to secrete hematopoietic growth factors, including GM-CSF and IL-3, in response to mitogens; 2)While many hematopoietic growth factors are secreted by several cell types, IL-3 appears to be secreted only by T cells, and only by direct stimulation of calcium dependent intracellular pathways via the CD3/TCR complex; and 3) Proliferating hematopoietic progenitor cells stimulate the proliferation and activation of a subset of T cells which function as hematopoietic suppressor cells, perhaps through the CD2 stimulated secretion of TNFalpha. Taken together, these studies demonstrate the roles for T cells activated by specific cell surface receptors in the differential secretion of hematopoietic growth factors and cytokines which modulate hematopoietic stem cell proliferation. We propose to pursue each of the major findings to date, by: 1)identifying the T cell specific molecular mechanisms regulating the transcription of the IL-3 gene; 2)Elucidating the mechanisms responsible for the preferential secretion of hematopoietic suppressive cytokines by activated T cells; and 3)Analyzing the extent, mechanisms and manipulability of the T cell CSF defect following allogeneic bone marrow transplantation. These studies will deepen our understanding of the specific molecular mechanisms and roles by which T lymphocytes modulate hematopoiesis, and will directly relate these results to the clinical scenario of engraftment following allogeneic bone marrow transplantation.
