title: The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells.
abstract: Human T helper 17 (T(H)17) cells regulate host defense, autoimmunity, and tumor immunity. Although cytokines that control human T(H)17 cell development have been identified, the costimulatory molecules important for T(H)17 cell generation are unknown. Here, we found that the inducible costimulator (ICOS) was critical for the differentiation and expansion of human T(H)17 cells. Human cord blood contained a subset of CD161(+)CD4(+) T cells that were recent emigrants from the thymus, expressed ICOS constitutively, and were imprinted as T(H)17 cells through ICOS signaling. ICOS stimulation induced c-MAF, RORC2, and T-bet expression in these cells, leading to increased secretion of interleukin-21 (IL-21), IL-17, and interferon-γ (IFN-γ) compared with cells stimulated with CD28. Conversely, CD28 ligation abrogated ICOS costimulation, dampening RORC2 expression while promoting the expression of the aryl hydrocarbon receptor, which led to reduced secretion of IL-17 and enhanced production of IL-22 compared with cells stimulated with ICOS. Moreover, ICOS promoted the robust expansion of IL-17(+)IFN-γ(+) human T cells, and the antitumor activity of these cells after adoptive transfer into mice bearing large human tumors was superior to that of cells expanded with CD28. The therapeutic effectiveness of ICOS-expanded cells was associated with enhanced functionality and engraftment in vivo. These findings reveal a vital role for ICOS signaling in the generation and maintenance of human T(H)17 cells and suggest that components of this pathway could be therapeutically targeted to treat cancer or chronic infection and, conversely, that interruption of this pathway may have utility in multiple sclerosis and other autoimmune syndromes. These findings have provided the rationale for designing new clinical trials for tumor immunotherapy.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. paulosc@mail.med.upenn.edu
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.forename: Gabriela
authors.initials: G
authors.lastname: Plesa
authors.forename: Megan M
authors.initials: MM
authors.lastname: Suhoski
authors.forename: Angel
authors.initials: A
authors.lastname: Varela-Rohena
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Golovina
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000502:physiology; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; C527203:KLRB1 protein, human; C495607:MAF protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051257:Proto-Oncogene Proteins c-maf; C539900:RORC protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D000098546:Interleukin-21