How Do CD4(+) T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?
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 MHCII(POS) and MHCII(NEG) 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 MHCII(POS) and MHCII(NEG) tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCII(POS) melanoma cells are directly killed by cytotoxic CD4(+) T cells in a perforin/granzyme B-dependent manner. By contrast, MHCII(NEG) myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4(+) T cells appears similar for MHCII(POS) and MHCII(NEG) tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Ole Audun Werner
OA
Haabeth
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Anders Aune
AA
Tveita
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Marte
M
Fauskanger
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Fredrik
F
Schjesvold
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Kristina Berg
KB
Lorvik
KG Jebsen Centre for Research on Influenza Vaccines, Institute of Immunology, Oslo University Hospital, University of Oslo , Oslo , Norway.
Peter O
PO
Hofgaard
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Hilde
H
Omholt
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway.
Ludvig A
LA
Munthe
Faculty of Dentistry, Molecular Genetics Laboratory, Department of Oral Biology, University of Oslo , Oslo , Norway.
Zlatko
Z
Dembic
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway ; Department of Biosciences, University of Oslo , Oslo , Norway ; Tumor Immunology Group, Department of Pathology, Oslo University Hospital, University of Oslo , Oslo , Norway.
Alexandre
A
Corthay
Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo , Oslo , Norway ; KG Jebsen Centre for Research on Influenza Vaccines, Institute of Immunology, Oslo University Hospital, University of Oslo , Oslo , Norway.
Bjarne
B
Bogen
CD4+ T cells; MHC class II; T cell receptor transgenic; T helper 1; multiple myeloma; transgenic mouse models; tumor antigen; tumor immunology