Monoclonal Antibodies as Probes for T Cell Activation

Shevach, E M.

Abstract

The major objective of our studies is to characterize cell surface structures on T lymphocytes which, in addition to the antigen- specific receptor (TCR), play critical roles both in vivo and in vitro in the process of lymphocyte activation. The TCR as well as other cell surface antigens of Thy-1+ dendritic epidermal T cells (DETC), a unique population of cells comprising 1-2% of murine epidermis, have been extensively characterized. DETC bear exclusively gamma delta-TCR; a combination of biochemical and molecular approaches has shown that both the TCR gamma-chain and the TCR delta-chain expressed by this population of cells exhibits considerable diversity. A panel of monoclonal antibodies (mAbs) has been generated against DETC. One mAb recognizes a cell surface disulfide linked dimer of 85 kD under non-reducing conditions. In the presence of phorbol esters, this mAb is a potent stimulator of T cell activation. Its biochemical and functional properties suggest that this mAb identifies the murine homologue of the human CD28 antigen. A second group of mAbs identify members of the Integrin Superfamily of Cell Adhesion Molecules (I-SCAM). These mAbs specifically inhibit the binding of DETC to a number of extracellular matrix proteins. We have also continued our studies of the Thy-1 and Ly-6 antigens which are coupled to the cell membrane via a phosphatidylinositol (PI) linkage. We have obtained evidence for additional PI-linked proteins which may play important roles in cell-cell interaction. An Ly-6 linked gene has been cloned and shown by transfection studies to be Ly-6A.2. Lastly, we have shown that T lymphocytes can be activated in vivo by allogeneic cells in the presence of the immunosuppressive drug, Cyclosporin A (Cy A) and that this activation process is independent of any of the known Interleukins.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000224-08
• Application #: 3818143
• Support Year: 8
• Fiscal Year: 1988

Institution

• Name: Niaid Extramural Activities
• Country: United States

Publications

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