Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation

Gareth Wyn Jones, Jason S. Stumhofer, Tom Foster, Jason Peter Twohig, Paul Hertzog, Nicholas Topley, Anwen Sian Williams, Christopher A. Hunter, Brendan J. Jenkins, Edward Chung Yern Wang, Simon Arnett Jones

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Tumor necrosis factor (TNF)-like cytokine (TL1A) is a T-cell costimulator that bolsters cytokine-induced activation through death receptor 3 (DR3). To explore the relationship between T-cell activation and TL1A responsiveness, flow cytometry profiled DR3 expression in resting and activated T cells. In human CD4+ T cells, DR3 was induced rapidly following activation and expressed prominently by interleukin (IL)-17-secreting T cells (Th17). Splenic T cells from wild-type and DR3-deficient mice showed that TL1A activation of DR3 inhibits Th17 generation (81$2.6% at 100 ng/ml TL1A) from naive T cells. This response was not associated with suppression of T-cell proliferation. Using neutralizing antibodies or T cells derived from genetically modified mice, TL1A inhibition of Th17 development was found to be independent of IL-2, IL-27, gammaIFN, IFNAR1, and STAT1. Under suboptimal TCR activation, TL1A continued to block IL-17A secretion, however, the reduced threshold of TCR engagement was now linked with an increase in TL1A-driven proliferation. In contrast, fully committed Th17 cells displayed an altered TL1A responsiveness and in the absence of TCR costimulation supported the maintenance of T cell IL-17A expression. Consequently, TL1A orchestrates unique outcomes in naive and effector T-helper cells, which may affect the proliferation, differentiation and maintenance of Th17 cells in peripheral compartments and inflamed tissues.--Jones, G. W., Stumhofer, J. S., Foster, T., Twohig, J.P., Hertzog, P., Topley, N., Williams, A. S., Hunter, C. A., Jenkins, B. J., Wang, E. C. Y., Jones, S. A. Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation.
Original languageUndefined/Unknown
Pages (from-to)409-419
Number of pages11
JournalFASEB Journal
Volume25
Issue number1
Publication statusPublished - 1 Jan 2011

Keywords

  • Cytokine
  • T-cell regulation
  • Inflammation

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