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Functional Dichotomy in CD40 Reciprocally Regulates Effector T Cell Functions¹

National Centre for Cell Science, Ganeshkhind, Pune, India

Activation of T cells requires signals through Ag-specific TCR and costimulatory molecules such as CD40L. Although the use of defined tumor Ags for the induction of protective T cells met with limited success, the CD40-CD40L interaction that was proposed to induce antitumor T cells did not prevent tumor growth completely. Using a model for prostate tumor, a leading cause of tumor-induced mortality in men, we show that the failure is due to a novel functional dichotomy of CD40 whereby it self-limits its antitumor functions by inducing IL-10. IL-10 prevents the CD40-induced CTL and TNF- and IL-12 production, Th1 skewing, and tumor regression. Priming mice with tumor lysate-pulsed IL-10-deficient dendritic cells (DCs) or wild-type DC plus anti-IL-10 Ab establishes antitumor memory T cells that can transfer the protection into syngenic nude mice. Infusion of Ag-pulsed IL-10-deficient but not wild-type DCs back into syngenic mice results in successful therapeutic autovaccination. Thus, we demonstrate the IL-10-sensitive antitumor T cell memory formulating a novel prophylactic and therapeutic principle.

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¹ The work was supported by the Department of Biotechnology, Government of India. R.A. is supported by an Indian Council of Medical Research fellowship.

² Address correspondence and reprint requests to Dr. Bhaskar Saha, National Centre for Cell Science, Ganeshkhind, Pune 411007, India. E-mail address: sahab{at}nccs.res.in

³ Abbreviations used in this paper: DC, dendritic cell; TNP, trinitrophenyl; KLH, keyhole limpet hemocyanin.