The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+ and CD8+ T-cell immunity

Twohig, Jason Peter, Marsden, Morgan, Cuff, Simone ORCID: https://orcid.org/0000-0002-0546-3579, Ferdinand, John R., Gallimore, Awen Myfanwy ORCID: https://orcid.org/0000-0001-6675-7004, Perks, William Victor, Al-Shamkhani, Aymen, Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337 and Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964 2012. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+ and CD8+ T-cell immunity. The FASEB Journal 26 (8) , pp. 3575-3586. 10.1096/fj.11-200618

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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 (DR3KO) mice and their DR3WT 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 DR3KO 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 DR3KO 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.—Twohig, J. P., Marsden, M., Cuff, S. M., Ferdinand, J. R., Gallimore, A. M., Perks, W. V., Al-Shamkhani, A., Humphreys, I. R., Wang, E. C. Y. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+ and CD8+ T-cell immunity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology Q Science > QR Microbiology > QR355 Virology
Uncontrolled Keywords:	murine cytomegalovirus; vaccinia virus
Publisher:	Federation of American Society of Experimental Biology
ISSN:	0892-6638
Last Modified:	04 Mar 2023 02:48
URI:	https://orca.cardiff.ac.uk/id/eprint/37369

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