Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin

Dennis D. Taub, William J Murphy, Osamu Asai, Robert G. Fenton, Gary Peltz, Michael L. Key, Susan Turcovski-Corrales, Dan L. Longo

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Signaling through the CD28 molecule on T cells by its natural ligand, B7, on APCs has recently been shown to require the presence of an active phosphatidylinositol 3-kinase pathway to mediate some of its costimulatory activities (1-7). Using the phosphatidylinositol 3-kinase inhibitor, wortmannin (WN) (8), on human and murine T cells, we have inhibited B7-1-mediated T cell activation and induced Ag-specific tolerance. The addition of WN and/or the B7-1 antagonist, CTLA4Ig, to primary human T cell cultures stimulated with B7-1-transfected allogeneic melanoma cell lines inhibited the generation of alloantigen-specific proliferative and cytolytic responses in vitro. Subsequent examination of these WN- and CTLA4Ig-treated primary T cell cultures revealed that these lymphocyte populations were tolerized to rechallenge with the priming alloantigens in secondary cultures in the absence of additional inhibitor(s). However, reactivity to a third party allogeneic stimulator remained intact. This WN-induced tolerance was reversed by the addition of high dose IL-2, but not IL-4 or IL-7, to the primary cultures, indicating that T cell anergy, not deletion, was responsible for this phenomenon. In vivo studies using a murine graft-vs-host disease (GVHD) model demonstrated that WN treatment of allogeneic donor lymphocytes in vitro failed to generate a significant GVHD in irradiated mouse recipients compared with control allogeneic donor lymphocytes. These findings suggest potentially novel therapeutic strategies for the prevention of GVHD.

Original languageEnglish (US)
Pages (from-to)2745-2755
Number of pages11
JournalJournal of Immunology
Volume158
Issue number6
StatePublished - Mar 15 1997
Externally publishedYes

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Isoantigens
T-Lymphocytes
Graft vs Host Disease
Phosphatidylinositol 3-Kinase
Lymphocytes
Interleukin-7
Primary Cell Culture
Interleukin-4
Interleukin-2
wortmannin
Melanoma
Cell Culture Techniques
Ligands
Cell Line
Population

ASJC Scopus subject areas

  • Immunology

Cite this

Taub, D. D., Murphy, W. J., Asai, O., Fenton, R. G., Peltz, G., Key, M. L., ... Longo, D. L. (1997). Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin. Journal of Immunology, 158(6), 2745-2755.

Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin. / Taub, Dennis D.; Murphy, William J; Asai, Osamu; Fenton, Robert G.; Peltz, Gary; Key, Michael L.; Turcovski-Corrales, Susan; Longo, Dan L.

In: Journal of Immunology, Vol. 158, No. 6, 15.03.1997, p. 2745-2755.

Research output: Contribution to journalArticle

Taub, DD, Murphy, WJ, Asai, O, Fenton, RG, Peltz, G, Key, ML, Turcovski-Corrales, S & Longo, DL 1997, 'Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin', Journal of Immunology, vol. 158, no. 6, pp. 2745-2755.
Taub, Dennis D. ; Murphy, William J ; Asai, Osamu ; Fenton, Robert G. ; Peltz, Gary ; Key, Michael L. ; Turcovski-Corrales, Susan ; Longo, Dan L. / Induction of Alloantigen-Specific T Cell Tolerance Through the Treatment of Human T Lymphocytes with Wortmannin. In: Journal of Immunology. 1997 ; Vol. 158, No. 6. pp. 2745-2755.
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