Death receptor 3 is essential for generating optimal protective CD4(+) T-cell immunity against Salmonella

Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, U.K.
European Journal of Immunology (Impact Factor: 4.03). 11/2011; 42. DOI: 10.1002/eji.201141950
Source: PubMed


The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2 and Th17-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L. TL1A expression was localized to splenic F4/80(+) macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4(+) -cell expansion. To address the relevance of the TL1A-DR3 interaction, we examined immune responses to S. enterica Typhimurium in mice lacking DR3. Infected DR3(-/-) mice harboured reduced numbers of antigen-experienced and proliferating CD4(+) T cells compared with wild-type mice. Furthermore, the frequency of IFN-ã(+) CD4(+) T cells in DR3(-/-) mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3(-/-) mice. This defect was intrinsic to CD4(+) T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3(-/-) CD4(+) T cells compared with wild-type CD4(+) -cell recipients. These data establish for the first time a role for DR3 in a host defence response.

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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 (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.
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    ABSTRACT: The recent article in Immunology from Parks et al. [1] entitled "Interleukin-32 enhances cytotoxic effect of natural killer cells to cancer cells via activation of death receptor 3" is very interesting, however, I believe that non-specialist readers would benefit from a more expansive and detailed discussion of its context. The authors have omitted much of the recent literature detailing the broader biological functions of Death Receptor 3 (DR3), most of which do not relate to regulating cell death. In addition, clarification is also required with regards to DR3's ligands as the older nomenclature can cause confusion and is particularly pertinent to the interpretation of this study. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd, Immunology.
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