IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells.
Regulatory T (T(reg)) cells play a key role in the maintenance of the immune system homeostasis. T(reg) cells can be generated in the periphery under control of TGF-beta, a cytokine involved in the negative control of the immune system. However, TGF-beta cooperates with IL-6 in the generation of Th17 cells, a novel class of effector cells involved in numerous inflammatory diseases, including colitis. Therefore, TGF-beta emerges as a mediator of both anti-inflammatory and pro-inflammatory processes, depending on the local cytokine milieu. Here we demonstrate that IL-21, a type-1 cytokine produced by T cells and involved in the pathogenesis of immune-mediated diseases, prevents the TGF-beta-dependent expression of FoxP3, the master regulator of T(reg) cell commitment, and the induction of suppressive capacity in naive CD4(+) T cells, while promoting the differentiation of Th17 cells. In vivo, CD4(+) naive T cells activated in the presence of TGF-beta and IL-21 failed to suppress colitis while inducing an inflammatory response characterized by high levels of IL-17 and RORgammat, the transcription factor expressed by Th17 cells. Therefore, IL-21 emerges as a key modulator of TGF-beta signaling, leading to the reciprocal differentiation of T(reg) and Th17 cells.
Fantini
Massimo C
MC
Division of Gastroenterology, University of Rome Tor Vergata, Rome, Italy. m.fantini@med.unroma2.it
Rizzo
Agelamaria
A
Fina
Daniele
D
Caruso
Roberta
R
Becker
Christoph
C
Neurath
Markus F
MF
Macdonald
Thomas T
TT
Pallone
Francesco
F
Monteleone
Giovanni
G
D019264:Adoptive Transfer; D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21