Distinct regulation of interleukin-17 in human T helper lymphocytes.
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.


CONCLUSIONS
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.
Chen
Zhi
Z
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
Tato
Cristina M
CM
Muul
Linda
L
Laurence
Arian
A
O'Shea
John J
JJ
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
D020381:Interleukin-17