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

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.—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.org