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(Journal of Leukocyte Biology. 2002;72:921-931.)
© 2002 by Society for Leukocyte Biology

Role of CD80, CD86, and CTLA4 on mouse CD4⁺ T lymphocytes in enhancing cell-cycle progression and survival after activation with PMA and ionomycin

Department of Biochemistry, Indian Institute of Science, Bangalore, India

Correspondence: Dipankar Nandi, Ph.D., Assistant Professor, Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India. E-mail: nandi{at}biochem.iisc.ernet.in

Cell surface interactions between the T cell costimulatory receptors, CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA4), with their cognate ligands, CD80 and CD86, on antigen-presenting cells play an important role in T cell activation. Although CD80 and CD86 are induced on T cells after activation, not much is known about their role in modulating T cell function. We show that CD80, CD86, and CTLA4 are induced on purified CD4⁺ T cells after in vitro activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and they play an essential role for proliferation and survival. Blockade of CTLA4-CD80/CD86 interactions greatly reduces PMA and ionomycin-mediated mouse CD4⁺ T cell activation. The three key features of this inhibition of activation are: First, late events in T cell activation (after 18 h) are affected; second, these cells do not undergo anergy; and third, CD4⁺CD25⁺ regulatory T cells are not responsible. Activation of T cells with PMA and ionomycin together with CTLA4-CD80/CD86 blockade results in decreased induction of CD25 and Bcl-X_L, reduced interleukin (IL)-2, and enhanced transforming growth factor-ß (TGF-ß) production. Furthermore, extended CTLA4-CD80/CD86 blockade results in decreased cell-cycle progression and enhanced apoptosis in a large proportion of cells. This inhibition of T cell proliferation can be rescued completely with anti-CD28 or IL-2 and partially with TGF-ß antagonists. This study reveals a functional role for CD80, CD86, and CTLA4 on CD4⁺ T lymphocytes and sheds light on the mechanisms by which these molecules enhance activation and survival with PMA and ionomycin.

Key Words: costimulation • apoptosis • transforming growth factor-ß • antigen-presenting cells

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