Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation

Fang, Lei; Adkins, Becky; Deyev, Vadim; Podack, Eckhard R.

doi:10.1084/jem.20072528

Cited by 156 publications

(227 citation statements)

References 41 publications

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“…Consistent with these findings transgenic mice that constitutively express TL1A have increased levels of IL-13 and IL-17 but not IFN-g under steady-state conditions [15,16]. However, other studies have shown that addition of TL1A or agonist anti-DR3 mAb enhances the production of both IL-4 and IFN-g during in vitro activation of naïve CD4 1 T cells [5,14]. To decipher the role of DR3 in host immunity to infection, we have examined the immune response against Salmonella enterica serovar Typhimurium in DR3-deficient mice.…”

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confidence: 65%

“…Furthermore, reports describing a role for DR3 in Th1-cell responses are conflicting. In vitro, CD4 1 T cells that cannot signal via DR3 are defective in the secretion of a number of cytokines including IL-2, IL-4, IL-5, IL-13, IL-10, IL-17, but not IFN-g [5,14]. Furthermore, addition of TL1A enhanced the proliferation of in vitro generated Th17 cells upon re-stimulation, but had no effect on the proliferation of Th1 cells [13].…”

Section: Introductionmentioning

confidence: 99%

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Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

et al. 2012

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The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2-and Th17-cell-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 1 macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4 1 -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 À/À mice harboured reduced numbers of antigen-experienced and proliferating CD4 1 T cells compared with WT mice. Furthermore, the frequency of IFN-c 1 CD4 1 T cells in DR3 À/À mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3 À/À mice. This defect was intrinsic to CD4 1 T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3 À/À CD4 1 T cells compared with WT CD4 1 -cell recipients. These data establish for the first time a role for DR3 in a host defence response.Key words: Costimulation . DR3 . Th1 cells . TNF receptor superfamily . TNFRSF25 Supporting Information available online IntroductionMembers of the tumour necrosis factor receptor superfamily (TNFRSF), such as CD27, CD30, OX40 and 4-1BB, are key players in the regulation of T-cell-mediated immune responses [1,2]. Collectively, these receptors provide costimulatory signals to antigen-stimulated T cells that enhance their expansion and survival. Thus, costimulation by various members of the TNFRSF augments the magnitude of the primary and/or secondary T-cell response and contributes to host protection against infection [3,4]. The involvement of different TNFRSF members in regulating T-cell responses varies however, with some TNFRSF members contributing preferentially towards enhanced memory generation [3] or local responses within the inflamed tissue [5]. The requirement for multiple TNFRSF members probably arises due to distinct temporal patterns of costimulatory receptor and ligand expression, which are likely to be controlled by factors such as pathogen type and virulence [4,6].Death receptor 3 (DR3, TNFRSF25) is a member of the TNFRSF that is most similar in sequence to TNFR1 [7]. DR3 Eur. J. Immunol. 2012. 42: 580-588 580 contains a death domain that binds to TRADD (TNFR1-associated death domain protein), a component of the TNFR1 signalosome that is capable of recruiting pro-caspase 8 as well as activating NF-kB [7]. Unlike TNFR1 however, which is widely expressed, expression of DR3 is limited primarily to T cells, cells of the monocyte/macrophage lineage and lymphoid tissue inducer (LTi) cells [8][9][10]. DR3 interacts with TL1A (TNFSF15), a TNF-like protein that is expressed on activated macrophages,...

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confidence: 65%

Section: Introductionmentioning

confidence: 99%

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

et al. 2012

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“…TNFR superfamily (TNFRSF)25, a member of the TNFR superfamily, is a type I transmembrane protein that has a cytoplasmic death domain with homology to TNFR1 (2-7). TNFRSF25 is expressed primarily by T lymphocytes, including CD4 + , CD8 + , and NKT cells (3)(4)(5)(6)(7)(8) and is efficiently upregulated after TCR stimulation. The natural ligand for TNFRSF25 was identified as TNF superfamily member 15 (TL1A) (9), which is a trimeric type II transmembrane protein that can be cleaved by metalloproteases and released as a functional and soluble trimer (10).…”

Section: S Everal Members Of the Tnf Superfamily Expressed By T Cellsmentioning

confidence: 99%

“…Cyclosporin A was purchased from Calbiochem/ EMD Millipore. Armenian hamster hybridoma producing Ab to mTNFRSF25 (agonist 4C12) was maintained as described previously (8). 4C12 (anti-TNFRSF25 agonist) and L4G6 (anti-mTL1A blocking mAb) was produced in hollow fiber bioreactors (Fibercell Systems) and purified from serumfree supernatants on a protein G column using PBS for elution.…”

Section: Flow Cytometry Abs and Reagentsmentioning

confidence: 99%

Cloning, Expression, and Functional Characterization of TL1A-Ig

Khan

Tsai

Schreiber

et al. 2013

The Journal of Immunology

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TNF superfamily member 15 (TL1A) is the ligand for TNFR superfamily (TNFRSF)25. We previously reported that TNFRSF25 stimulation with an agonist Ab, 4C12, expands pre-existing CD4+Foxp3+ regulatory T cells (Tregs) in vivo. To determine how the physiological ligand differs from the Ab, we generated a soluble mouse TL1A-Ig fusion protein that forms a dimer of TL1A trimers in solution with an apparent molecular mass of 516 kDa. In vitro, TL1A-Ig mediated rapid proliferation of Foxp3+ Tregs and a population of CD4+Foxp3− conventional T cells. TL1A-Ig also blocked de novo biogenesis of inducible Tregs and it attenuated the suppressive function of Tregs. TNFRSF25 stimulation by TL1A-Ig in vivo induced expansion of Tregs such that they increased to 30–35% of all CD4+ T cells in the peripheral blood within 5 d of treatment. Treg proliferation in vivo was dependent on TCR engagement with MHC class II. Elevated Treg levels can be maintained for at least 20 d with daily injections of TL1A-Ig. TL1A-Ig–expanded Tregs expressed high levels of activation/memory markers KLRG1 and CD103 and were highly suppressive ex vivo. TL1A-Ig–mediated Treg expansion in vivo was protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of conventional T cells to Tregs in the lung and blocking eosinophil exudation into the bronchoalveolar fluid. Thus, TL1A-Ig fusion proteins are highly active and tightly controllable agents to stimulate Treg proliferation in vivo, and they are uniquely able to maintain high levels of expanded Tregs by repeated administration.

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“…TL1A also promotes Treg proliferation and attenuates Treg-mediated suppression of non-regulatory CD4 1 T cells [9]. In addition, TL1A has been shown to costimulate invariant NKT cells [10] and may have a role in enhancing NK cell-mediated tumor cell killing [11]. …”

Section: Introductionmentioning

confidence: 99%

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity

et al. 2011

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TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNFlike protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD41 T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8 1 T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8 1 T-celldependent manner and renders mice immune to a subsequent challenge with tumor cells.To gain further insight into the role of TNFRSF25 in CD8 1 T-cell responses, we analyzed the effect of TNFRSF25 triggering on OT-I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen-specific CD8 1 T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8 1 T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8 1 T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8 1 T cells. Results and discussionEctopic expression of TL1A-mediates CD8 1 T-celldependent rejection of J558L tumorsThree transfected J558L tumor cell lines that express relatively high levels of TL1A (Fig. 1A) were combined immediately before inoculation into mice. In T-and B-cell-deficient SCID mice TL1A-expressing J558L tumor cells grew with similar kinetics to control J558L cells transfected with the empty vector (Fig. 1B). In sharp contrast, TL1A-expressing J558L cells, but not control tumor cells, were rejected in immune competent BALB/c mice, demonstrating that tumor rejection requires an adaptive immune response (Fig. 1C). In many cases, TL1A-expressing J558L tumors grew initially following s.c. injection into BALB/c mice, but these tumors regressed and the majority of animals had no detectable tumors 70 days after initial tumor inoculation (Fig. 1C). Mice that rejected the TL1A-expressing J558L tumors were immune to a subsequent challenge with non-transfected J558L tumor cells ( Fig. 1D and Supporting Information Fig. 1A). To assess the role of T-cell subsets in TL1A-mediated tumor rejection, we administered anti-CD4 or anti-CD8 depleting mAbs prior to inoculation with TL1A-expressing J558L tumor cells. Only depletion of CD8 1 T cells resulted in a significant and consistent prevention of tumor cell rejection ( Fig. 1E and Supporting Information Fig. 1B). These results demonstrate that ectopic expression of TL1A can lead to the generation of a protective anti-tumor immune response and implicate a role for TNFRSF25 on CD8 1 T cells in mediating this effect.TNFRSF25 triggering costimulates Ag-specific CD8 1 T cells in vitroTo define more precisely the role of TNFRSF25 triggering in CD8 1 T-cell responses, we used OVA-specific TCR transgenic OT-IT cells as a model to study the effects of ...

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Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation

Abstract: We identify the tumor necrosis factor receptor superfamily 25 (TNFRSF25)/TNFSF15 pair as critical trigger for allergic lung infl ammation, which is a cardinal feature of asthma.

Cited by 156 publications

References 41 publications

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Cloning, Expression, and Functional Characterization of TL1A-Ig

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity

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Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation

Abstract: We identify the tumor necrosis factor receptor superfamily 25 (TNFRSF25)/TNFSF15 pair as critical trigger for allergic lung infl ammation, which is a cardinal feature of asthma.

Cited by 156 publications

References 41 publications

Death receptor 3 is essential for generating optimal protective CD41 T‐cell immunity against Salmonella

Death receptor 3 is essential for generating optimal protective CD41 T‐cell immunity against Salmonella

Cloning, Expression, and Functional Characterization of TL1A-Ig

Triggering of TNFRSF25 promotes CD8+ T‐cell responses and anti‐tumor immunity

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Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity