title: Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation.
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, γIFN, 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.
authors.affiliation: Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, Wales, UK.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Jason S
authors.initials: JS
authors.lastname: Stumhofer
authors.forename: Tom
authors.initials: T
authors.lastname: Foster
authors.forename: Jason P
authors.initials: JP
authors.lastname: Twohig
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000494:pharmacology*; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D007376:Interleukin-2; D007378:Interleukins; D053219:Receptors, Tumor Necrosis Factor, Member 25; D016212:Transforming Growth Factor beta; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000098546:Interleukin-21
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