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- Title
Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress.
- Authors
Tindemans, Irma; Schoonhoven, Anne van; KleinJan, Alex; Bruijn, Marjolein J.W. de; Lukkes, Melanie; Nimwegen, Menno van; Branden, Anouk van den; Bergen, Ingrid M.; Corneth, Odilia B.J.; IJcken, Wilfred F.J. van; Stadhouders, Ralph; Hendriks, Rudi W.; van Schoonhoven, Anne; de Bruijn, Marjolein Jw; van Nimwegen, Menno; van den Branden, Anouk; Corneth, Odilia Bj; van IJcken, Wilfred Fj
- Abstract
Allergic asthma is mediated by Th2 responses to inhaled allergens. Although previous experiments indicated that Notch signaling activates expression of the key Th2 transcription factor Gata3, it remains controversial how Notch promotes allergic airway inflammation. Here we show that T cell-specific Notch deficiency in mice prevented house dust mite-driven eosinophilic airway inflammation and significantly reduced Th2 cytokine production, serum IgE levels, and airway hyperreactivity. However, transgenic Gata3 overexpression in Notch-deficient T cells only partially rescued this phenotype. We found that Notch signaling was not required for T cell proliferation or Th2 polarization. Instead, Notch-deficient in vitro-polarized Th2 cells showed reduced accumulation in the lungs upon in vivo transfer and allergen challenge, as Notch-deficient Th2 cells were retained in the lung-draining lymph nodes. Transcriptome analyses and sequential adoptive transfer experiments revealed that while Notch-deficient lymph node Th2 cells established competence for lung migration, they failed to upregulate sphingosine-1-phosphate receptor 1 (S1PR1) and its critical upstream transcriptional activator Krüppel-like factor 2 (KLF2). As this KLF2/S1PR1 axis represents the essential cell-intrinsic regulator of T cell lymph node egress, we conclude that the druggable Notch signaling pathway licenses the Th2 response in allergic airway inflammation via promoting lymph node egress.
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 7, p3576
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI128310