Journal
FRONTIERS IN IMMUNOLOGY
Volume 5, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2014.00174
Keywords
tumor immunology; CD4(+) T cells; MHC class II; T cell receptor transgenic; transgenic mouse models; tumor antigen; T helper 1; multiple myeloma
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Funding
- Norwegian Cancer Society
- Multiple Myeloma Research Foundation
- Research Council of Norway
- South-Eastern Norway Regional Health Authority
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CD4(+) T cells contribute to tumor eradication, even in the absence of CD8(+) T cells. Cytotoxic CD4(+) T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4(+) T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4(+) T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naive CD4(+) T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4(+) T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naive CD4(+) T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4(+) T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-gamma stimulated M1-like macrophages. In summary, while the priming phase of CD4(+) T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.
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