title: Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes.
abstract: The TNF-like cytokine TL1A augments IFN-gamma production by anti-CD3 plus anti-CD28 and IL-12/IL-18-stimulated peripheral blood (PB) T cells. However, only a small subset of PB T cells respond to TL1A stimulation with IFN-gamma production. PB CCR9+ T cells represent a small subset of circulating T cells with mucosal T cell characteristics and a Th1/Tr1 cytokine profile. In the current study, we show that TL1A enhanced IFN-gamma production by TCR- or CD2/CD28-stimulated CCR9(+)CD4+ PB T cells. However, TL1A had the most pronounced effect on augmenting IFN-gamma production by IL-12/IL-18-primed CCR9(+)CD4+ PB T cells. TL1A enhanced both the percentage and the mean fluorescence intensity of IFN-gamma in CCR9(+)CD4+ T cells as assessed by intracellular cytokine staining. IL-12 plus IL-18 up-regulated DR3 expression in CCR9(+)CD4+ T cells but had negligible effect on CCR9(-)CD4+ T cells. CCR9(+)CD4+ T cells isolated from the small intestine showed a 37- to 105-fold enhancement of IFN-gamma production when TL1A was added to the IL-12/IL18 cytokine combination. Cell membrane-expressed TL1A was preferentially expressed in CCR9(+)CD4+ PB T cells, and a blocking anti-TL1A mAb inhibited IFN-gamma production by cytokine-primed CCR9(+)CD4+ T cells by approximately 50%. Our data show that the TL1A/DR3 pathway plays a dominant role in the ultimate level of cytokine-induced IFN-gamma production by CCR9+ mucosal and gut-homing PB T cells and could play an important role in Th1-mediated intestinal diseases, such as Crohn's disease, where increased expression of IL-12, IL-18, TL1A, and DR3 converge in the inflamed intestinal mucosa.
authors.affiliation: Burns and Allen Research Institute, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90048, USA. papadakisk@cshs.org
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.forename: Daocheng
authors.initials: D
authors.lastname: Zhu
authors.forename: John L
authors.initials: JL
authors.lastname: Prehn
authors.forename: Carol
authors.initials: C
authors.lastname: Landers
authors.forename: Armine
authors.initials: A
authors.lastname: Avanesyan
authors.forename: Gina
authors.initials: G
authors.lastname: Lafkas
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003424:Crohn Disease / Q000209:etiology / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; C119309:CC chemokine receptor 9; D020382:Interleukin-18; D054388:Receptors, CCR; D019707:Receptors, Chemokine; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011994:Recombinant Proteins; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma