The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+and CD8+T‐cell immunity
Open Access
- 11 May 2012
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 26 (8), 3575-3586
- https://doi.org/10.1096/fj.11-200618
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. FASEB J. 26, 3575–3586 (2012). www.fasebj.orgKeywords
Funding Information
- Medical Research Council
- Wellcome Trust
- Medical Research Council (G0901119)
- Biotechnology and Biological Sciences Research Council
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