Differential CD40/CD40L expression results in counteracting antitumor immune responses.
Establishment of host-protective memory T cells against tumors is the objective of an antitumor immunoprophylactic strategy such as reinforcing T cell costimulation via CD40-CD40L interaction. Previous CD40-targeted strategies assumed that T cell costimulation is an all-or-none phenomenon. It was unknown whether different levels of CD40L expression induce quantitatively and qualitatively different effector T cell responses. Using mice expressing different levels of CD40L, we demonstrated that the greater the T cell CD40L expression the less tumor growth occurred; the antitumor T cell response was host-protective. Lower levels of CD40L expression on T cells induced IL-10-mediated suppression of tumor-regressing effector CD8(+) T cells and higher productions of IL-4 and IL-10. Using mice expressing different levels of CD40 or by administering different doses of anti-CD40 Ab, similar observations were recorded implying that the induction of protumor or antitumor T cell responses was a function of the extent of CD40 cross-linking. IL-10 neutralization during priming with tumor Ags resulted in a stronger tumor-regressing effector T cell response. Using IL-10(-/-) DC for priming of mice expressing different levels of CD40L and subsequent transfer of the T cells from the primed mice to nu/nu mice, we demonstrated the protumor role of IL-10 in the induction of tumor-promoting T cells. Our 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.
Murugaiyan
Gopal
G
National Centre for Cell Science, Pune, India.
Agrawal
Reena
R
Mishra
Gyan C
GC
Mitra
Debashis
D
Saha
Bhaskar
B
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D013045:Species Specificity
D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D016753:Interleukin-10; D023201:CD40 Ligand