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.
|Dilloo, D; Dirksen, U; Schneider, M et al. (1996) Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation. Exp Hematol 24:537-43|
|Levitt, L; Lin, R (1996) Biology and treatment of adult acute lymphoblastic leukemia. West J Med 164:143-55|
|Zehnder, J L; Shatsky, M; Leung, L L et al. (1995) Involvement of CD31 in lymphocyte-mediated immune responses: importance of the membrane-proximal immunoglobulin domain and identification of an inhibiting CD31 peptide. Blood 85:1282-8|
|Park, J H; Kaushansky, K; Levitt, L (1993) Transcriptional regulation of interleukin 3 (IL3) in primary human T lymphocytes. Role of AP-1- and octamer-binding proteins in control of IL3 gene expression. J Biol Chem 268:6299-308|
|Park, J H; Levitt, L (1993) Overexpression of mitogen-activated protein kinase (ERK1) enhances T-cell cytokine gene expression: role of AP1, NF-AT, and NF-KB. Blood 82:2470-7|
|Zehnder, J L; Hirai, K; Shatsky, M et al. (1992) The cell adhesion molecule CD31 is phosphorylated after cell activation. Down-regulation of CD31 in activated T lymphocytes. J Biol Chem 267:5243-9|
|Levitt, L J; Nagler, A; Lee, F et al. (1991) Production of granulocyte/macrophage-colony-stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 receptor and by the CD2 receptor. J Clin Invest 88:67-75|
|Burdach, S; Zessack, N; Dilloo, D et al. (1991) Differential regulation of lymphokine production by distinct subunits of the T cell interleukin 2 receptor. J Clin Invest 87:2114-21|
|Burdach, S; Zessack, N; Levitt, L (1989) Hematopoietic growth control by the T-cell CD2 determinant is exerted at a pretranslational level. Haematol Blood Transfus 32:416-22|
|Saigo, K; Shatsky, M; Levitt, L J et al. (1989) Interaction of histidine-rich glycoprotein with human T lymphocytes. J Biol Chem 264:8249-53|
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