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Differential CD40/CD40L expression results in counteracting antitumor immune responses.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2007 Feb 15; Vol. 178 (4), pp. 2047-55. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Animals
Antigens, Neoplasm immunology
Antigens, Neoplasm metabolism
CD40 Antigens biosynthesis
CD40 Ligand biosynthesis
CD8-Positive T-Lymphocytes metabolism
Dendritic Cells metabolism
Dose-Response Relationship, Immunologic
Gene Expression Regulation immunology
Immunity, Cellular
Interleukin-10 biosynthesis
Interleukin-10 deficiency
Mice
Mice, Nude
Neoplasms metabolism
Species Specificity
CD40 Antigens immunology
CD40 Ligand immunology
CD8-Positive T-Lymphocytes immunology
Dendritic Cells immunology
Interleukin-10 immunology
Neoplasms immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 178
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 17277108
- Full Text :
- https://doi.org/10.4049/jimmunol.178.4.2047