Human group 3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation

Yong Oon Ahn, Matthew A. Weeres, Marie Luise Neulen, Jahyang Choi, Seong Ho Kang, Dae Seog Heo, Rachel Bergerson, Bruce R. Blazar, Jeffrey S. Miller, Michael R. Verneris

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1β + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1β + IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1β+ IL-23, and IL-2 expanded ILC3s while IL-1β+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC3s maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use.

Original languageEnglish (US)
Pages (from-to)2335-2342
Number of pages8
JournalEuropean Journal of Immunology
Volume45
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • DR3
  • Human
  • IL-22
  • ILC3
  • TL1A

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