title: CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells.
abstract: CD4(+) T cells control the effector function, memory, and maintenance of CD8(+) T cells. Paradoxically, we found that absence of CD4(+) T cells enhanced adoptive immunotherapy of cancer when using CD8(+) T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4(+)CD25(-) Th cells (Th cells) with tumor/self-reactive CD8(+) T cells and vaccination into CD4(+) T cell-deficient hosts induced autoimmunity and regression of established melanoma. Transfer of CD4(+) T cells that contained a mixture of Th and CD4(+)CD25(+) T regulatory cells (T(reg) cells) or T(reg) cells alone prevented effective adoptive immunotherapy. Maintenance of CD8(+) T cell numbers and function was dependent on Th cells that were capable of IL-2 production because therapy failed when Th cells were derived from IL-2(-/-) mice. These findings reveal that Th cells can help break tolerance to a persisting self-Ag and treat established tumors through an IL-2-dependent mechanism, but requires simultaneous absence of naturally occurring T(reg) cells to be effective.
authors.affiliation: Division of Surgery, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Paul.Antony@nih.gov
authors.forename: Paul A
authors.initials: PA
authors.lastname: Antony
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.forename: Akgül
authors.initials: A
authors.lastname: Akpinarli
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Speiss
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Surman
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D006706:Homeostasis / Q000276:immunology; D007113:Immunity, Innate; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods; D007376:Interleukin-2 / Q000502:physiology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017634:Self Tolerance / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D023001:Transplantation Tolerance / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D058951:gp100 Melanoma Antigen
chemical_list: D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548642:Pmel protein, mouse; D015375:Receptors, Interleukin-2; D058951:gp100 Melanoma Antigen
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