Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but contrains Th17-mediated pathology

Autor: Claudia Ribeiro de Almeida, Marjan van Meurs, Jan Piet van Hamburg, Janneke N. Samsom, Rudi W. Hendriks, Louis Boon, Marjolein J. W. de Bruijn, Edwin F. E. de Haas, Marloes van Zwam
Přispěvatelé: Clinical Immunology and Rheumatology, Immunology, Pediatrics
Rok vydání: 2008
Předmět:
Genetically modified mouse
STAT3 Transcription Factor
Pathology
medicine.medical_specialty
Encephalomyelitis
Autoimmune
Experimental
Receptors
Retinoic Acid
Immunology
Down-Regulation
Mice
Transgenic
Suppressor of Cytokine Signaling Proteins
Autoimmunity
GATA3 Transcription Factor
Biology
T-helper cells
Myelin oligodendrocyte glycoprotein
Interferon-gamma
Mice
Th2 Cells
RAR-related orphan receptor gamma
Transforming Growth Factor beta
medicine
Transcription factors
Immunology and Allergy
Animals
STAT3
Transcription factor
STAT4
Receptors
Thyroid Hormone
NFATC Transcription Factors
Interleukin-6
Interleukin-17
GATA3
Cell Differentiation
Nuclear Receptor Subfamily 1
Group F
Member 3
STAT4 Transcription Factor
Th1 Cells
Animal models
Suppressor of Cytokine Signaling 3 Protein
biology.protein
Interleukin-2
Cytokines
Interleukin 17
Interleukin-4
Zdroj: European journal of immunology, 38(9), 2573-2586. Wiley-VCH Verlag
European Journal of Immunology, 38, 2573-2586. Wiley-VCH
ISSN: 1521-4141
0014-2980
Popis: 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.
Databáze: OpenAIRE
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