Divergent roles for CD4+ T cells in the priming and effector/memory phases of adoptive immunotherapy.
The requirement for CD4(+) Th cells in the cross-priming of antitumor CTL is well accepted in tumor immunology. Here we report that the requirement for T cell help can be replaced by local production of GM-CSF at the vaccine site. Experiments using mice in which CD4(+) T cells were eliminated, either by Ab depletion or by gene knockout of the MHC class II beta-chain (MHC II KO), revealed that priming of therapeutic CD8(+) effector T cells following vaccination with a GM-CSF-transduced B16BL6-D5 tumor cell line occurred independently of CD4(+) T cell help. The adoptive transfer of CD8(+) effector T cells, but not CD4(+) effector T cells, led to complete regression of pulmonary metastases. Regression of pulmonary metastases did not require either host T cells or NK cells. Transfer of CD8(+) effector T cells alone could cure wild-type animals of systemic tumor; the majority of tumor-bearing mice survived long term after treatment (>100 days). In contrast, adoptive transfer of CD8(+) T cells to tumor-bearing MHC II KO mice improved survival, but eventually all MHC II KO mice succumbed to metastatic disease. WT mice cured by adoptive transfer of CD8(+) T cells were resistant to tumor challenge. Resistance was mediated by CD8(+) T cells in mice at 50 days, while both CD4(+) and CD8(+) T cells were important for protection in mice challenged 150 days following adoptive transfer. Thus, in this tumor model CD4(+) Th cells are not required for the priming phase of CD8(+) effector T cells; however, they are critical for both the complete elimination of tumor and the maintenance of a long term protective antitumor memory response in vivo.
Hu
H M
HM
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
Winter
H
H
Urba
W J
WJ
Fox
B A
BA
D019264:Adoptive Transfer; D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation; D019496:Cancer Vaccines / Q000276:immunology; D002452:Cell Count; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012880:Skin Pigmentation / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
D000955:Antigens, T-Independent; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II