The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells

Arianne C. Richard, Cuiyan Tan, Eric T. Hawley, Julio Gomez-Rodriguez, Ritobrata Goswami, Xiang Ping Yang, Anthony C. Cruz, Pallavi Penumetcha, Erika T. Hayes, Martin Pelletier, Odile Gabay, Matthew Walsh, John R. Ferdinand, Andrea Keane-Myers, Yongwon Choi, John J. O'Shea, Aymen Al-Shamkhani, Mark Kaplan, Igal Gery, Richard M. SiegelFrançoise Meylan

Research output: Contribution to journalArticle

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Abstract

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.

Original languageEnglish (US)
Pages (from-to)3567-3582
Number of pages16
JournalJournal of Immunology
Volume194
Issue number8
DOIs
StatePublished - Apr 15 2015

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Tumor Necrosis Factor Ligand Superfamily Member 15
Receptors, Tumor Necrosis Factor, Member 25
Interleukin-9
Virulence
T-Lymphocytes
Interleukin-4
Cytokines
Interleukin-13
T-Lymphocyte Subsets
Lung Diseases
Autoimmune Diseases
Interleukin-2
Pneumonia
Lymphocytes
Pathology
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. / Richard, Arianne C.; Tan, Cuiyan; Hawley, Eric T.; Gomez-Rodriguez, Julio; Goswami, Ritobrata; Yang, Xiang Ping; Cruz, Anthony C.; Penumetcha, Pallavi; Hayes, Erika T.; Pelletier, Martin; Gabay, Odile; Walsh, Matthew; Ferdinand, John R.; Keane-Myers, Andrea; Choi, Yongwon; O'Shea, John J.; Al-Shamkhani, Aymen; Kaplan, Mark; Gery, Igal; Siegel, Richard M.; Meylan, Françoise.

In: Journal of Immunology, Vol. 194, No. 8, 15.04.2015, p. 3567-3582.

Research output: Contribution to journalArticle

Richard, AC, Tan, C, Hawley, ET, Gomez-Rodriguez, J, Goswami, R, Yang, XP, Cruz, AC, Penumetcha, P, Hayes, ET, Pelletier, M, Gabay, O, Walsh, M, Ferdinand, JR, Keane-Myers, A, Choi, Y, O'Shea, JJ, Al-Shamkhani, A, Kaplan, M, Gery, I, Siegel, RM & Meylan, F 2015, 'The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells', Journal of Immunology, vol. 194, no. 8, pp. 3567-3582. https://doi.org/10.4049/jimmunol.1401220
Richard, Arianne C. ; Tan, Cuiyan ; Hawley, Eric T. ; Gomez-Rodriguez, Julio ; Goswami, Ritobrata ; Yang, Xiang Ping ; Cruz, Anthony C. ; Penumetcha, Pallavi ; Hayes, Erika T. ; Pelletier, Martin ; Gabay, Odile ; Walsh, Matthew ; Ferdinand, John R. ; Keane-Myers, Andrea ; Choi, Yongwon ; O'Shea, John J. ; Al-Shamkhani, Aymen ; Kaplan, Mark ; Gery, Igal ; Siegel, Richard M. ; Meylan, Françoise. / The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. In: Journal of Immunology. 2015 ; Vol. 194, No. 8. pp. 3567-3582.
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abstract = "The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.",
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AU - Hawley, Eric T.

AU - Gomez-Rodriguez, Julio

AU - Goswami, Ritobrata

AU - Yang, Xiang Ping

AU - Cruz, Anthony C.

AU - Penumetcha, Pallavi

AU - Hayes, Erika T.

AU - Pelletier, Martin

AU - Gabay, Odile

AU - Walsh, Matthew

AU - Ferdinand, John R.

AU - Keane-Myers, Andrea

AU - Choi, Yongwon

AU - O'Shea, John J.

AU - Al-Shamkhani, Aymen

AU - Kaplan, Mark

AU - Gery, Igal

AU - Siegel, Richard M.

AU - Meylan, Françoise

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