The major objectives of our studies are to characterize cell surface structures on T lymphocytes and on accessory cells which play critical roles both in vivo and in vitro in the process of lymphocyte activation : 1) We have developed monoclonal antibodies (mAb) to a T lymphocyte activation antigen and demonstrated in biochemical studies that it is the vitronectin receptor (VNR) which is capable of interacting with the extracellular matrix (ECM) proteins -vitronectin, fibronectin, and fibrinogen. The VNR appears to play a critical role as an accessory molecule for a subpopulation of T cells which express the gamma/delta T cell receptor (TCR). Gamma/delta T cell lines and hybridomas which express the C(gamma)4, V(delta)6 chains appear to recognize an autoantigen; however, activation of these lines requires that, in addition, to engagement of the TCR by antigen, the VNR must also bind to its ligand on ECM-proteins. 2) We cloned a cDNA for a cell surface disulfide linked 44 kD dimer (Ly-49) which is a member of a large multigene family and which is expressed on rare T cell tumors. We have mapped the gene which encodes this antigen to the short arm of mouse chromosome 6 near the gene which encodes the murine natural killer (NK) cell marker, NK1.1. Ly-49 also may play a role in NK cell function because 30% of highly purified NK cells express Ly-49; it is also possible that NK1.1 is a member of the Ly-49 multigene family. 3) In continuing studies of cell surface antigens which are coupled to the membrane via a phosphatidylinositol (PI) linkage, we have shown that mAbs to the human CD59 antigen are capable of inducing human T cell proliferation and cytokine production in the presence of phorbol ester and a crosslinking second antibody. 4) In order to probe the cellular mechanisms whereby the administration of the immunosuppressive drug, Cyclosporine A (CsA) induces autoimmune disease, we have established a model in which autoantibodies to gastric mucosal antigens can be induced in the offspring of mothers treated only during pregnancy with CsA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000224-09
Application #
3809579
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Zhu, Jinfang; Davidson, Todd S; Wei, Gang et al. (2009) Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med 206:329-41
Huter, Eva N; Stummvoll, Georg H; DiPaolo, Richard J et al. (2009) Pre-differentiated Th1 and Th17 effector T cells in autoimmune gastritis: Ag-specific regulatory T cells are more potent suppressors than polyclonal regulatory T cells. Int Immunopharmacol 9:540-5
Huter, Eva N; Punkosdy, George A; Glass, Deborah D et al. (2008) TGF-beta-induced Foxp3+ regulatory T cells rescue scurfy mice. Eur J Immunol 38:1814-21
Shevach, Ethan M; Tran, Dat Q; Davidson, Todd S et al. (2008) The critical contribution of TGF-beta to the induction of Foxp3 expression and regulatory T cell function. Eur J Immunol 38:915-7
Stummvoll, Georg H; DiPaolo, Richard J; Huter, Eva N et al. (2008) Th1, Th2, and Th17 effector T cell-induced autoimmune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells. J Immunol 181:1908-16
Shevach, Ethan M (2006) From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25:195-201
Mendel, Itzhak; Shevach, Ethan M (2006) Activated T cells express the OX40 ligand: requirements for induction and costimulatory function. Immunology 117:196-204
Sereti, Irini; Imamichi, Hiromi; Natarajan, Ven et al. (2005) In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. J Clin Invest 115:1839-47
Allen, Stacey; Read, Simon; DiPaolo, Richard et al. (2005) Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells. J Immunol 175:5759-64
DiPaolo, Richard J; Glass, Deborah D; Bijwaard, Karen E et al. (2005) CD4+CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol 175:7135-42

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