Front. Immunol., 15 April 2014 |

How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

  • 1Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, University of Oslo, Oslo, Norway
  • 2KG Jebsen Centre for Research on Influenza Vaccines, Institute of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway
  • 3Faculty of Dentistry, Molecular Genetics Laboratory, Department of Oral Biology, University of Oslo, Oslo, Norway
  • 4Department of Biosciences, University of Oslo, Oslo, Norway
  • 5Tumor Immunology Group, Department of Pathology, Oslo University Hospital, University of Oslo, Oslo, Norway

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.

Keywords: tumor immunology, CD4+ T cells, MHC class II, T cell receptor transgenic, transgenic mouse models, tumor antigen, T helper 1, multiple myeloma

Citation: Haabeth OAW, Tveita AA, Fauskanger M, Schjesvold F, Lorvik KB, Hofgaard PO, Omholt H, Munthe LA, Dembic Z, Corthay A and Bogen B (2014) How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules? Front. Immunol. 5:174. doi: 10.3389/fimmu.2014.00174

Received: 17 February 2014; Paper pending published: 07 March 2014;
Accepted: 02 April 2014; Published online: 15 April 2014.

Edited by:

Fang-Ping Huang, Imperial College London, UK

Reviewed by:

Luca Gattinoni, National Cancer Institute, USA
Junko Matsuzaki, Roswell Park Cancer Institute, USA
William J. Magner, Roswell Park Cancer Institute, USA

Copyright: © 2014 Haabeth, Tveita, Fauskanger, Schjesvold, Lorvik, Hofgaard, Omholt, Munthe, Dembic, Corthay and Bogen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bjarne Bogen, Institute of Immunology, University of Oslo, OUS Rikshospitalet HF, A2/A3, Sognsvannsveien 20, Oslo N-0027, Norway e-mail:

Ole Audun Werner Haabeth and Anders Aune Tveita have contributed equally to this work.