title: Tumour-specific CD4 T cells eradicate melanoma via indirect recognition of tumour-derived antigen.
abstract: The importance of CD4 T cells in tumour immunity has been increasingly recognised, with recent reports describing robust CD4 T cell-dependent tumour control in mice whose immune-regulatory mechanisms have been disturbed by irradiation, chemotherapy, immunomodulatory therapy and/or constitutive immunodeficiency. Tumour control in such models has been attributed in large part to direct Major Histocompatibility Complex (MHC) class II-dependent CD4 T cell killing of tumour cells. To test whether CD4 T cells can eradicate tumours without directly killing tumour cells, we developed an animal model in which tumour-derived antigen could be presented to T-cell receptor (TCR)-transgenic CD4 T cells by host but not tumour MHC class II molecules. In I-E(+) mice bearing I-E(null) tumours, naive I-E-restricted CD4 T cells proliferated locally in tumour-draining lymph nodes after recognising tumour-derived antigen on migratory dendritic cells. In lymphopaenic but not immunosufficient hosts, CD4 T cells differentiated into polarised T helper type 1 (Th1) cells expressing interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and interleukin (IL)-2 but little IL-17, and cleared established tumours. Tumour clearance was enhanced by higher TCR affinity for tumour antigen-MHC class II and was critically dependent on IFNγ, as demonstrated by early tumour escape in animals treated with an IFNγ blocking antibody. Thus, CD4 T cells and IFNγ can control tumour growth without direct T-cell killing of tumour cells, and without requiring additional adaptive immune cells such as CD8 T cells and B cells. Our results support a role for effective CD4 T cell-dependent tumour immunity against MHC class II-negative tumours.
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Shklovskaya
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Terry
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Guy
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Buckley
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Bolton
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Erhua
authors.initials: E
authors.lastname: Zhu
authors.affiliation: Origins of Cancer Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.affiliation: T Cell Biology Research Program, Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia.|Discipline of Dermatology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazekas de St. Groth
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma
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