Role of CD 40 in the regulation of anti tumor immune response

Abstract

Activation of T cells requires signals through antigen-specific T cell receptor and costimulatory molecules such as CD40-ligand (CD40-L). While the use of defined tumor antigens for the induction of protective T cells met with a limited success, CD40-CD40-L interaction that was proposed to induce anti-tumor T cells did not prevent tumor growth completely. Using a model for prostate tumor, a leading cause of tumor-induced mortality in men, it has been shown here that the failure is due to a novel functional dichotomy of CD40 whereby it self-limits its anti-tumor functions by inducing interleukin-10. Interleukin-10 prevents the CD40-induced cytotoxic T cells (CTL) and TNF-α and interleukin-12 production, Th1 skewing and tumor regression. Priming mice with tumor lysate-pulsed interleukin-10-deficient DCs or wild-type DC plus antiinterleukin- 10 antibody establishes anti-tumor memory T cells that can transfer the protection into syngenic nude mice. Infusion of antigen-pulsed interleukin-10-deficient but not wild-type DCs back into syngenic mice results in successful therapeutic autovaccination. Having addressed a novel functional dichotomy of CD40 whereby it induces anti-tumor T cells and a pro-tumor cytokine, interleukin-10, the underlying mechanism for the observed duality in CD40 function has been deciphered using mice expressing different levels of CD40 or CD40-L and different doses of anti-CD40 antibody. Using mice expressing different levels of CD40 or CD40-L and different doses of anti-CD40 antibody, it has been shown that greater the T cell CD40-L expression less is the tumor growth and host-protective is the anti-tumor T cell response. Lower CD40-L expression induced higher IL-10 production, and a parallel IL-4-dominated response, IL- 10-sensitive effector T cells and suppressed tumor-regressing T cells. Thus the results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.