The major objective of this project is to study the cell biology and molecular control of erythropoietic immunoregulation. We propose 3 interrelated lines of investigation: (1) We hypothesize that IL2 regulates cellular production and release of specific erythropoietic growth factors and that this regulation is mediated by differential interaction with alternative IL2- receptor (IL2R). IL2 stimulates erythroid burst-promoting activity (BPA) from resting T cell and NK cells A 70KD IL2R has been identified in the absence of Tac antigen on resting T and NK cells. GM-CSF and IL3 have potent BPA. We will assess effects of IL2 on T and NK cell GM-CSF and IL3 gene expression and protein secretion. We will examine whether IL2-induced stimulation of erythropoiesis is mediated by the 70KD IL2R. In the presence of Tac IL2R+ T cells, IL2 as a potent inhibitor of erythropoiesis IF gamma, TNF-beta and transforming growth factor-beta (TGF-beta) all suppress erythropoiesis. Based on this data, IL2 modulation of IF gamma, TNF-beta and TGF-beta gene expression and protein secretion from Tac IL2R+ T cells will be assessed. (2) The T cell CD2 receptor mediates an alternative pathway of T cell activation- CD2 blockade suppresses activated T cell IL2R expression and decrease IL2- induced IF gamma release as well as IL2-induced erythroid suppression. We hypothesize that CD2 modulates T cell erythropoietic immunoregulation. We will assess how triggering CD2 with a defined ligand, or with CD2-activating monoclonal antibodies, modulates T cell growth factor production and erythroid regulation. We will investigate whether antigen-receptor (CD3) and CD2 determinants function together to modulate T cell activation, lymphokine release and synthesis of erythroid growth factors. (3) Many questions remain regarding the identity of physiologic ligands mediating function via the T cell alternate pathway. Rosette formation between human T cells and sheep RBC is mediated by the CD2 receptor. We have shown that histidine-rich-glycoprotein (HRGP) inhibits rosette formation and binds specifically and reversibly to T cell. HRGP and modulates IL2R expression, IF gamma release and erythroid suppression from activated T cells. Our hypothesis is that HRGP is a natural ligand for an epitope closely related to CD2 and that it can modulate T cell activation.
Our aim i s to study HRGP-T cell structure-function relationships. We will characterize the HRGP receptor on T cells and the ability of HRGP to modulate CD3-induced or CD2-mediated T cell activation and regulatory functions. These studies should provide new information in the biology of hematopoietic immunoregulation and are relevant to our understanding of T cell membrane biology and T cell activation.
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