Abstract
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 naïve 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, naïve 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-γ 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.
Highlights
Tissue antigenmajor histocompatibility complex (MHC) CLASS II STATUS OF TUMOR CELLS USED IN TUMOR IMMUNOLOGY STUDIES FOCUSED ON THE ROLE OF CD4+ T CELLS CD4+ T cells recognize peptides (about 13–17aa long) bound to the groove of MHC class II molecules [59] on professional antigenpresenting cells (APCs) (B cells, dendritic cells, macrophages, in addition to thymic epithelial cells) [60,61,62]
Ole Audun Werner Haabeth1†, Anders Aune Tveita1†, Marte Fauskanger 1, Fredrik Schjesvold 1, Kristina Berg Lorvik 1, Peter O
Transfer of CD4+ T cells that first had been primed in vitro could readily reject B16 tumors [37, 38]. These findings indicate that major histocompatibility complex (MHC) IIPOS tumor cells themselves are incapable of stimulating naïve tyrosinase-related protein 1 (Trp1)-specific CD4+ T cells, and that priming by professional host antigen-presenting cell (APC) is required
Summary
MHC CLASS II STATUS OF TUMOR CELLS USED IN TUMOR IMMUNOLOGY STUDIES FOCUSED ON THE ROLE OF CD4+ T CELLS CD4+ T cells recognize peptides (about 13–17aa long) bound to the groove of MHC class II molecules [59] on professional antigenpresenting cells (APCs) (B cells, dendritic cells, macrophages, in addition to thymic epithelial cells) [60,61,62]. In certain cells, MHC class II molecules may be induced by interferon gamma (IFN-γ) stimulation [63, 64]. In CD4+ T cell immune responses to tumors, the MHC class II status of the tumor cells is of importance. The antigen-specific interaction between CD4+ T cells and MHC IIPOS tumor cells is conceptually easy to grasp. The basis for antigen presentation and anti-tumor effector mechanisms are less obvious in the context of MHC IINEG tumors [25, 26, 31, 70] – because such cancer cells cannot directly stimulate. Transgenic models, where the T cell specificity is known and both naïve and primed CD4+ T cells are readily available
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