title: The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4⁺ and CD8⁺ T-cell immunity.
abstract: Death receptor 3 (DR3, TNFRSF25), the closest family relative to tumor necrosis factor receptor 1, promotes CD4(+) T-cell-driven inflammatory disease. We investigated the in vivo role of DR3 and its ligand TL1A in viral infection, by challenging DR3-deficient (DR3(KO)) mice and their DR3(WT) littermates with the β-herpesvirus murine cytomegalovirus or the poxvirus vaccinia virus. The phenotype and function of splenic T-cells were analyzed using flow cytometry and molecular biological techniques. We report surface expression of DR3 by naive CD8(+) T cells, with TCR activation increasing its levels 4-fold and altering the ratio of DR3 splice variants. T-cell responses were reduced up to 90% in DR3(KO) mice during acute infection. Adoptive transfer experiments indicated this was dependent on T-cell-restricted expression of DR3. DR3-dependent CD8(+) T-cell expansion was NK and CD4 independent and due to proliferation, not decreased cell death. Notably, impaired immunity in DR3(KO) hosts on a C57BL/6 background was associated with 4- to 7-fold increases in viral loads during the acute phase of infection, and in mice with suboptimal NK responses was essential for survival (37.5%). This is the first description of DR3 regulating virus-specific T-cell function in vivo and uncovers a critical role for DR3 in mediating antiviral immunity.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Twohig
authors.forename: Morgan
authors.initials: M
authors.lastname: Marsden
authors.forename: Simone M
authors.initials: SM
authors.lastname: Cuff
authors.forename: John R
authors.initials: JR
authors.lastname: Ferdinand
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
authors.forename: William V
authors.initials: WV
authors.lastname: Perks
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: Ian R
authors.initials: IR
authors.lastname: Humphreys
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D006566:Herpesviridae Infections / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000502:physiology*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000502:physiology*; D019562:Viral Load
chemical_list: D053219:Receptors, Tumor Necrosis Factor, Member 25; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15