Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses

• Published in: Journal of Immunology 2007-02, Vol.178 (4), p.2047-2055
• Main Authors: Murugaiyan, Gopal, Agrawal, Reena, Mishra, Gyan C, Mitra, Debashis, Saha, Bhaskar
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; CD40 Antigens - biosynthesis; CD40 Antigens - immunology; CD40 Ligand - biosynthesis; CD40 Ligand - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dose-Response Relationship, Immunologic; Gene Expression Regulation - immunology; Immunity, Cellular; Interleukin-10 - biosynthesis; Interleukin-10 - deficiency; Interleukin-10 - immunology; Mice; Mice, Nude; Neoplasms - immunology; Neoplasms - metabolism; Species Specificity
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.4.2047

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.