Functional dichotomy in CD40 reciprocally regulates effector T cell functions.
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-alpha 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.
Murugaiyan
Gopal
G
National Centre for Cell Science, Ganeshkhind, Pune, India.
Agrawal
Reena
R
Mishra
Gyan C
GC
Mitra
Debashis
D
Saha
Bhaskar
B
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D004306:Dose-Response Relationship, Immunologic; D007156:Immunologic Memory / Q000235:genetics; D016219:Immunotherapy, Adoptive; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D019013:CD40 Antigens; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12