TL1A Selectively Enhances IL-12/IL-18-Induced NK Cell Cytotoxicity against NK-Resistant Tumor Targets

Heidemann, Stephanie C.; Chavez, Valerie; Landers, Carol J.; Kucharzik, Torsten; Prehn, John; Targan, Stephan R.

doi:10.1007/s10875-010-9382-9

Cited by 27 publications

(24 citation statements)

References 31 publications

(34 reference statements)

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“…TL1A biases T cells to differentiate towards Th1 and Th17 phenotype [12], [13], [17] and modulates Treg expansion and functions [18]–[20]. Moreover, DR3 can modulate NK [6], [21] and NKT-cell functions [22]. Consistently, recent studies have reported an essential role for the TL1A/DR3 pathway in generating T-cell host defense response [23], [24].…”

Section: Introductionmentioning

confidence: 53%

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

et al. 2013

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Death receptor (DR3) 3 is a member of the TNFR superfamily. Its ligand is TNF-like ligand 1A (TL1A), a member of the TNF superfamily. TL1A/DR3 interactions have been reported to modulate the functions of T cells, NK, and NKT cells and play a crucial role in driving inflammatory processes in several T-cell-dependent autoimmune diseases. However, TL1A expression and effects on B cells remain largely unknown. In this study, we described for the first time that B cells from human blood express significant amounts of DR3 in response to B cell receptor polyclonal stimulation. The relevance of these results has been confirmed by immunofluorescence analysis in tonsil and spleen tissue specimens, which showed the in situ expression of DR3 in antigen-stimulated B cells in vivo. Remarkably, we demonstrated that TL1A reduces B-cell proliferation induced by anti-IgM-antibodies and IL-2 but did not affect B-cell survival, suggesting that TL1A inhibits the signal(s) important for B-cell proliferation. These results revealed a novel function of TL1A in modulating B-cell proliferation in vitro and suggest that TL1A may contribute to homeostasis of effector B-cell functions in immune response and host defense, thus supporting the role of the TL1A/DR3 functional axis in modulating the adaptive immune response.

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Section: Introductionmentioning

confidence: 53%

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

et al. 2013

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“…IL-18 is known to activate NK and T cells through its receptor-mediated signaling to produce IFN-γ, contributing to Th1 cell development (50, 67). Additionally, IL-18 enhances NK cell cytotoxicity, Fas ligand-mediated Th1 cell cytotoxicity, and proliferation of activated T cells (67, 68). In the parasite-infected mice, parallel to IL-18 induction, IL-12 is produced at increased levels as infection progresses (see Figs.…”

Section: Discussionmentioning

confidence: 99%

TLR9 and MyD88 Are Crucial for the Development of Protective Immunity to Malaria

Gowda

2012

The Journal of Immunology

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Effective resolution of malaria infection by avoiding pathogenesis requires regulated pro- to anti-inflammatory responses and the development of protective immunity. TLRs are known to be critical for initiating innate immune responses, but their roles in the regulation of immune responses and development of protective immunity to malaria remain poorly understood. In this study, using WT, TLR2−/−, TLR4−/−, TLR9−/−, and MyD88−/− mice infected with P. yoelii, we show that TLR9 and MyD88 regulate pro-/anti-inflammatory cytokines, Th1/Th2 development, and cellular and humoral responses. DCs from TLR9−/− and MyD88−/− mice produced significantly lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines than DCs from WT mice. NK and CD8+ T cells from TLR9−/− and MyD88−/− mice showed markedly impaired cytotoxic activity. Further, mice deficient in TLR9 and MyD88 showed higher Th2 type and lower Th1 type IgGs. Consequently, TLR9−/− and MyD88−/− mice exhibited compromised ability to control parasitemia and were susceptible to death. Our data also show that TLR9 and MyD88 distinctively regulate immune responses to malaria infection. TLR9−/− but not MyD88−/− mice produced significant levels of both pro- and anti-inflammatory cytokines, including IL-1β and IL-18, by other TLRs/inflammasome- and/or IL-1R/IL-18R-mediated signaling. Thus, while MyD88−/− mice completely lacked cell-mediated immunity, TLR9−/− mice showed low levels of cell-mediated immunity and were slightly more resistant to malaria infection than MyD88−/− mice. Overall, our findings demonstrate that TLR9 and MyD88 play central roles in the immune regulation and development of protective immunity to malaria, and have implications in understanding immune responses to other pathogens.

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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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TL1A Selectively Enhances IL-12/IL-18-Induced NK Cell Cytotoxicity against NK-Resistant Tumor Targets

Cited by 27 publications

References 31 publications

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

TLR9 and MyD88 Are Crucial for the Development of Protective Immunity to Malaria

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

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TL1A Selectively Enhances IL-12/IL-18-Induced NK Cell Cytotoxicity against NK-Resistant Tumor Targets

Cited by 27 publications

References 31 publications

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

TLR9 and MyD88 Are Crucial for the Development of Protective Immunity to Malaria

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

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