The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells.

Type 2 innate lymphoid cells (ILC2s) are part of a large family of ILCs that are important effectors in innate immunity, lymphoid organogenesis, and tissue remodeling. ILC2s mediate parasite expulsion but also contribute to airway inflammation, emphasizing the functional similarity between these cells and Th2 cells. Consistent with this, we report that the transcription factor GATA3 was highly expressed by human ILC2s. CRTH2(+) ILC2s were enriched in nasal polyps of patients with chronic rhinosinusitis, a typical type 2-mediated disease. Nasal polyp epithelial cells expressed TSLP, which enhanced STAT5 activation, GATA3 expression, and type 2 cytokine production in ILC2s. Ectopic expression of GATA3 in Lin(-)CD127(+)CRTH2(-) cells resulted in induction of CRTH2 and the capacity to produce high amounts of type 2 cytokines in response to TSLP plus IL-33. Hence, we identify GATA3, potently regulated by TSLP, as an essential transcription factor for the function of human ILC2s.

[1]  H. Kita,et al.  IL-33–Responsive Lineage−CD25+CD44hi Lymphoid Cells Mediate Innate Type 2 Immunity and Allergic Inflammation in the Lungs , 2012, The Journal of Immunology.

[2]  S. Ziegler,et al.  TSLP enhances the function of helper type 2 cells , 2011, European journal of immunology.

[3]  Hergen Spits,et al.  Innate lymphoid cells: emerging insights in development, lineage relationships, and function. , 2012, Annual review of immunology.

[4]  W. Paul,et al.  How are TH2-type immune responses initiated and amplified? , 2010, Nature Reviews Immunology.

[5]  W. Paul,et al.  An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation. , 2011, International immunology.

[6]  F. Grosveld,et al.  GATA-3 promotes maturation, IFN-gamma production, and liver-specific homing of NK cells. , 2003, Immunity.

[7]  Fumio Takei,et al.  Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. , 2012, Immunity.

[8]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[9]  Marjolein J. W. de Bruijn,et al.  Pulmonary innate lymphoid cells are major producers of IL‐5 and IL‐13 in murine models of allergic asthma , 2012, European journal of immunology.

[10]  B. Blom,et al.  STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression , 2005, Nature Immunology.

[11]  Shinichiro Sawa,et al.  Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. , 2008, Immunity.

[12]  Dirk E. Smith,et al.  Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. , 2012, The Journal of allergy and clinical immunology.

[13]  Yusuke Nakamura,et al.  Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells. , 2009, American journal of respiratory cell and molecular biology.

[14]  Ya-Jen Chang,et al.  Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity , 2011, Nature Immunology.

[15]  R. Coffman,et al.  New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-251 , 2002, The Journal of Immunology.

[16]  W. Fokkens,et al.  Role of Innate Immunity in the Pathogenesis of Chronic Rhinosinusitis: Progress and New Avenues , 2012, Current Allergy and Asthma Reports.

[17]  M. Leach,et al.  IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. , 2001, Immunity.

[18]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[19]  H. Spits,et al.  The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling , 2011, Nature Immunology.

[20]  J. Lennerz,et al.  A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity , 2009, Nature.

[21]  H. Spits,et al.  Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells , 2010, The Journal of experimental medicine.

[22]  R. Locksley,et al.  Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity , 2011, Nature Immunology.

[23]  茂呂 和世.  Innate production of T[H]2 cytokines by adipose tissue-associated c-Kit[+]Sca-1[+] lymphoid cells , 2010 .

[24]  Yu Wang,et al.  TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand , 2005, The Journal of experimental medicine.

[25]  Yongwon Choi,et al.  An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells , 2004, Nature Immunology.

[26]  R. de Waal Malefyt,et al.  Human Thymic Stromal Lymphopoietin Preferentially Stimulates Myeloid Cells1 , 2001, The Journal of Immunology.

[27]  A. McKenzie,et al.  Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity , 2010, Nature.

[28]  David Voehringer,et al.  The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. , 2012, Immunity.

[29]  Hergen Spits,et al.  Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161 , 2011, Nature Immunology.

[30]  H. D. Liggitt,et al.  Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice , 2005, Nature Immunology.

[31]  Freddy Radtke,et al.  Rorα is essential for nuocyte development , 2011, Nature Immunology.

[32]  K. Zhao,et al.  IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells , 2009, Proceedings of the National Academy of Sciences.

[33]  A. Murphy,et al.  Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. , 2008, Immunity.

[34]  A. McKenzie,et al.  Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. , 2012, The Journal of allergy and clinical immunology.

[35]  A. McKenzie,et al.  Insights into the initiation of type 2 immune responses , 2011, Immunology.

[36]  F. Grosveld,et al.  GATA-3 Promotes Maturation, IFN-γ Production, and Liver-Specific Homing of NK Cells , 2003 .

[37]  David Artis,et al.  Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus , 2011, Nature Immunology.

[38]  B. Blom,et al.  Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B. , 2006, Blood.

[39]  S. Ziegler,et al.  Sensing the outside world: TSLP regulates barrier immunity , 2010, Nature Immunology.

[40]  David J. Erle,et al.  Systemically dispersed innate IL-13–expressing cells in type 2 immunity , 2010, Proceedings of the National Academy of Sciences.