TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
Studies have shown that transforming growth factor-beta (TGF-beta) and interleukin 6 (IL-6) are required for the lineage commitment of pathogenic IL-17-producing T helper cells (T(H)-17 cells). Unexpectedly, here we found that stimulation of myelin-reactive T cells with TGF-beta plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. Cells stimulated with TGF-beta plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. Hence, TGF-beta and IL-6 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of T(H)-17 cells. Our findings suggest that full acquisition of pathogenic function by effector T(H)-17 cells is mediated by IL-23 rather than by TGF-beta and IL-6.
McGeachy
Mandy J
MJ
Schering-Plough Biopharma, Palo Alto, California 94304, USA.
Bak-Jensen
Kristian S
KS
Chen
Yi
Y
Tato
Cristina M
CM
Blumenschein
Wendy
W
McClanahan
Terrill
T
Cua
Daniel J
DJ
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D013601:T-Lymphocytes / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer; D016212:Transforming Growth Factor beta / Q000502:physiology*
D020381:Interleukin-17; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D016753:Interleukin-10