Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but constrains Th17-mediated pathology.
The zinc-finger transcription factor GATA3 serves as a master regulator of T-helper-2 (Th2) differentiation by inducing expression of the Th2 cytokines IL-4, IL-5 and IL-13 and by suppressing Th1 development. Here, we investigated how GATA3 affects Th17 differentiation, using transgenic mice with enforced GATA3 expression. We activated naïve primary T cells in vitro in the presence of transforming growth factor-beta and IL-6, and found that enforced GATA3 expression induced co-expression of Th2 cytokines in IL-17-producing T cells. Although the presence of IL-4 hampered Th17 differentiation, transforming growth factor-beta/IL-6 cultures from GATA3 transgenic mice contained substantial numbers of IL-17(+) cells, partially because GATA3 supported Th17 differentiation by limiting IL-2 and IFN-gamma production. GATA3 additionally constrained Th17 differentiation in vitro through IL-4-independent mechanisms, involving downregulating transcription of STAT3, STAT4, NFATc2 and the nuclear factor RORgammat, which is crucial for Th17 differentiation. Remarkably, upon myelin oligodendrocyte glycoprotein immunization in vivo, GATA3 transgenic mice contained similar numbers of IL-17-producing T cells in their lymph nodes as wild-type mice, but were not susceptible to autoimmune encephalomyelitis, possibly due to concomitant production of IL-4 and IL-10 induction. We therefore conclude that although GATA3 allows Th17 differentiation, it acts as an inhibitor of Th17-mediated pathology, through IL-4-dependent and IL-4-independent pathways.
van Hamburg
Jan Piet
JP
Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
de Bruijn
Marjolein J W
MJ
Ribeiro de Almeida
Claudia
C
van Zwam
Marloes
M
van Meurs
Marjan
M
de Haas
Edwin
E
Boon
Louis
L
Samsom
Janneke N
JN
Hendriks
Rudi W
RW
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D015850:Interleukin-6; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma