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Published online before print March 23, 2005

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(Journal of Leukocyte Biology. 2005;78:144-157.)
© 2005 by Society for Leukocyte Biology

CTLA4-CD80/CD86 interactions on primary mouse CD4⁺ T cells integrate signal-strength information to modulate activation with Concanavalin A

Department of Biochemistry, Indian Institute of Science (IISc), Bangalore, India

¹ Correspondence: #126, Department of Biochemistry, Indian Institute of Science, Bangalore, 560012 India. E-mail: nandi{at}biochem.iisc.ernet.in

The mechanisms by which concanavalin A (Con A), a lectin, activates T cells are poorly studied. A low dose of Con A is stimulatory for T cells, whereas a high dose of Con A results in suppression of proliferation and enhanced T cell death. The expression and functional roles of costimulatory receptors, CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA4), and their ligands, CD80 and CD86, on primary mouse CD4⁺ T cells after activation with different doses of Con A were studied. CTLA4-CD80/CD86 interactions in this T:T cell activation model demonstrate distinct outcomes depending on the dose of Con A. CTLA4-CD80/CD86 interactions inhibit CD4⁺ T cell cycling and survival after activation with a suppressive dose of Con A by increasing oxidative stress and decreasing levels of BclX_L. The enhanced CD4⁺ T cell death with a suppressive dose of Con A is dependent on excess H₂O₂ and nitric oxide but is independent of Fas and caspase activity. It is surprising that the increased proliferation of CD4⁺ T cells with a suppressive dose of Con A on blocking CTLA4-CD80/CD86 interactions is largely interleukin (IL)-2-independent but is cyclosporine A-sensitive. On activation with a stimulatory dose of Con A, CTLA4-CD80/CD86 interactions enhance T cell activation and survival by reducing the production of reactive oxygen species, increasing IL-2 and BclX_L levels. Here IL-10 but not transforming growth factor-ß plays a functional role. In summary, CTLA4-CD80/CD86 interactions on T cells integrate signal strength, based on the dose of Con A, to enhance or inhibit primary mouse CD4⁺ T cell cycling and survival.

Key Words: costimulation • T cell cycling and survival • IL-2-independent • oxidative stress • IL-10 • TGF-ß

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