Zhi Chen1, Cristina M Tato, Linda Muul, Arian Laurence, John J O'Shea. 1. National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-1820, USA. chenzhi@mail.nih.gov
Abstract
OBJECTIVE: Interleukin-17 (IL-17)-producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid-related orphan receptor gammat (RORgammat). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive human CD4+ T cells of cytokines known to promote murine Th17 cells. METHODS: Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction. RESULTS: In response to anti-CD3/anti-CD28 stimulation alone, human memory T cells rapidly produced IL-17, whereas naive T cells expressed low levels. Transforming growth factor beta1 and IL-6 up-regulated RORgammat expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL-23 up-regulated its own receptor and was an important inducer of IL-17 and IL-22. CONCLUSION: The present data demonstrate the differential regulation of IL-17 and RORgammat expression in human CD4+ T cells compared with murine cells. Optimal conditions for the development of IL-17-producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL-23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.
OBJECTIVE:Interleukin-17 (IL-17)-producing T helper cells have been proposed to represent a separate lineage of CD4+ cells, designated Th17 cells, which are regulated by the transcription factor retinoic acid-related orphan receptor gammat (RORgammat). However, despite advances in understanding murine Th17 differentiation, a systematic assessment of factors that promote the differentiation of naive human T cells to Th17 cells has not been reported. The present study was undertaken to assess the effects on naive humanCD4+ T cells of cytokines known to promote murine Th17 cells. METHODS:Human naive and memory CD4+ T cells isolated from peripheral blood were activated and cultured with various cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay and flow cytometry. Messenger RNA was measured by quantitative polymerase chain reaction. RESULTS: In response to anti-CD3/anti-CD28 stimulation alone, human memory T cells rapidly produced IL-17, whereas naive T cells expressed low levels. Transforming growth factor beta1 and IL-6 up-regulated RORgammat expression but did not induce Th17 differentiation of naive CD4+ T cells. However, IL-23 up-regulated its own receptor and was an important inducer of IL-17 and IL-22. CONCLUSION: The present data demonstrate the differential regulation of IL-17 and RORgammat expression in humanCD4+ T cells compared with murine cells. Optimal conditions for the development of IL-17-producing T cells from murine naive precursors are ineffective in human T cells. Conversely, IL-23 promoted the generation of human Th17 cells but was also a very potent inducer of other proinflammatory cytokines. These findings may have important implications in the pathogenesis of human autoimmunity as compared with mouse models.
Authors: Richard H Duerr; Kent D Taylor; Steven R Brant; John D Rioux; Mark S Silverberg; Mark J Daly; A Hillary Steinhart; Clara Abraham; Miguel Regueiro; Anne Griffiths; Themistocles Dassopoulos; Alain Bitton; Huiying Yang; Stephan Targan; Lisa Wu Datta; Emily O Kistner; L Philip Schumm; Annette T Lee; Peter K Gregersen; M Michael Barmada; Jerome I Rotter; Dan L Nicolae; Judy H Cho Journal: Science Date: 2006-10-26 Impact factor: 47.728
Authors: Yi Chen; Claire L Langrish; Brent McKenzie; Barbara Joyce-Shaikh; Jason S Stumhofer; Terrill McClanahan; Wendy Blumenschein; Tatyana Churakovsa; Justin Low; Leonard Presta; Christopher A Hunter; Robert A Kastelein; Daniel J Cua Journal: J Clin Invest Date: 2006-05 Impact factor: 14.808
Authors: Sophie Hue; Philip Ahern; Sofia Buonocore; Marika C Kullberg; Daniel J Cua; Brent S McKenzie; Fiona Powrie; Kevin J Maloy Journal: J Exp Med Date: 2006-10-09 Impact factor: 14.307
Authors: Marika C Kullberg; Dragana Jankovic; Carl G Feng; Sophie Hue; Peter L Gorelick; Brent S McKenzie; Daniel J Cua; Fiona Powrie; Allen W Cheever; Kevin J Maloy; Alan Sher Journal: J Exp Med Date: 2006-10-09 Impact factor: 14.307
Authors: Birgit Fogal; Tai Yi; Chen Wang; Deepak A Rao; Amir Lebastchi; Sanjay Kulkarni; George Tellides; Jordan S Pober Journal: J Immunol Date: 2011-11-14 Impact factor: 5.422
Authors: Anna U Bielinska; Michele Gerber; Luz P Blanco; Paul E Makidon; Katarzyna W Janczak; Michael Beer; Benjamin Swanson; James R Baker Journal: Crit Rev Immunol Date: 2010 Impact factor: 2.214
Authors: Louis Y A Chai; Frank van de Veerdonk; Renoud J Marijnissen; Shih-Chin Cheng; Ai Leng Khoo; Magda Hectors; Katrien Lagrou; Alieke G Vonk; Johan Maertens; Leo A B Joosten; Bart-Jan Kullberg; Mihai G Netea Journal: Immunology Date: 2009-12-02 Impact factor: 7.397