CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells

• Published in: The Journal of immunology (1950) 2005-03, Vol.174 (5), p.2591-2601
• Main Authors: Antony, Paul A, Piccirillo, Ciriaco A, Akpinarli, Akgul, Finkelstein, Steven E, Speiss, Paul J, Surman, Deborah R, Palmer, Douglas C, Chan, Chi-Chao, Klebanoff, Christopher A, Overwijk, Willem W, Rosenberg, Steven A, Restifo, Nicholas P
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; gp100 Melanoma Antigen; Homeostasis - immunology; Immunity, Innate; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Interleukin-2 - physiology; Interleukin-2 - therapeutic use; Lymphocyte Activation - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - immunology; Receptors, Interleukin-2 - biosynthesis; Self Tolerance - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - transplantation; Transplantation Tolerance - immunology; Tumor Escape - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.5.2591

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.