Distinct regulation of interleukin-17 in human T helper lymphocytes
Article first published online: 30 AUG 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 9, pages 2936–2946, September 2007
How to Cite
Chen, Z., Tato, C. M., Muul, L., Laurence, A. and O'Shea, J. J. (2007), Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis & Rheumatism, 56: 2936–2946. doi: 10.1002/art.22866
- Issue published online: 30 AUG 2007
- Article first published online: 30 AUG 2007
- Manuscript Accepted: 1 JUN 2007
- Manuscript Received: 14 FEB 2007
- Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
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 γt (RORγt). 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.
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.
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 β1 and IL-6 up-regulated RORγt 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.
The present data demonstrate the differential regulation of IL-17 and RORγt 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.