Dominant Role for TL1A/DR3 Pathway in IL-12 plus IL-18-Induced IFN-γ Production by Peripheral Blood and Mucosal CCR9+ T Lymphocytes

Papadakis, Konstantinos A.; Zhu, Daocheng; Prehn, John; Landers, Carol J.; Avanesyan, Armine; Lafkas, Gina; Targan, Stephan R.

doi:10.4049/jimmunol.174.8.4985

Cited by 109 publications

(107 citation statements)

References 28 publications

(45 reference statements)

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“…Similar effects were recently reported in studies of human lymphocytes (9,13,15,23). This study further explored the specific role that TL1A plays in the pathways that lead to production of IFN-␥.…”

Section: Discussionsupporting

confidence: 60%

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Bamias

Mishina

Nyce

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

164

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TL1A is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-␥ and may, therefore, participate in the development of T helper-1-type effector responses. In this study, we investigated whether interactions between TL1A and DR3 are involved in the pathogenesis of chronic murine ileitis. We demonstrate that alternative splicing of DR3 mRNA takes place during the activation of lymphocytes, which results in up-regulation of the complete͞transmembrane (tm) form of DR3. Using two immunogenetically distinct animal models of Crohn's disease, we demonstrate that induction of intestinal inflammation is associated with significant up-regulation of TL1A and tm DR3 in the inflamed mucosa. In addition, within isolated lamina propria mononuclear cells from mice with inflammation, TL1A is primarily expressed on CD11c high dendritic cells. We also report that TL1A acts preferentially on memory CD4 ؉ ͞CD45RB lo murine lymphocytes by significantly inducing their proliferation, whereas it does not affect the proliferation of the naïve CD4 ؉ ͞ CD45RB hi T helper cell subpopulation. Finally, we demonstrate that TL1A synergizes with both the cytokine-dependent IL-12͞IL-18 pathway and with low-dose stimulation of the T cell receptor to significantly induce the secretion of IFN-␥ via an IL-18-independent pathway. Our results raise the possibility that interaction(s) between TL1A expressed on antigen-presenting cells and tm DR3 on lymphocytes may be of particular importance for the pathogenesis of chronic inflammatory conditions that depend on IFN-␥ secretion, including inflammatory bowel disease. Blockade of the TL1A͞DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.Crohn's disease ͉ cytokines ͉ mucosal inflammation T he differentiation of naïve CD4 ϩ lymphocytes into IFN-␥-secreting Th1 ''effector'' cells is a multistep process that involves several cell types, costimulatory molecules, transcription factors, and secreted cytokines (1). Antigen-presenting cell (APC)-derived IL-12 is essential for the induction of IFN-␥, an effect that is greatly enhanced by IL-18 (2). IL-12 up-regulates T-bet, a transcription factor that is critical for the stabilization of a T helper (Th)1-polarized phenotype (3). Recently, additional cytokines that play prominent roles during Th1 responses have been described, such as IL-27 and IL-23 (4). Engagement of the T cell receptor (TCR) provides further signals for the induction of IFN-␥, both in parallel to and independently of cytokinemediated pathways (1).Members of the TNF and TNF-receptor superfamilies of proteins (TNFSFPs and TNFRSFPs, respectively) are abundantly expressed in the immune system, and are critically involved in the differentiation, proliferation, and apoptosis of immune cells (5). Several members of these families induce secretion of IFN-␥ upon ligand͞receptor binding, thereby enhancing Th1-type responses (6-8). TL1A (TNFSPF15) is a r...

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Section: Discussionsupporting

confidence: 60%

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Bamias

Mishina

Nyce

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

164

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“…44 On the other hand, it was also reported that the binding of TL1a to DR3 expressed on human T cells caused increased IFNg production and promoted Th1 differentiation in vitro. 45,46 Our data suggest that the major effects of the activation of DR3 signaling in vivo were caused by the expansion and activation of Tregs in donor mice.…”

Section: Discussionmentioning

confidence: 92%

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Kim

Nishikii

Baker

et al. 2015

Blood

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Key Points• Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells.• T cells from DR3 antibodytreated donors result in reduced acute GVHD and preserved GVT effects. numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from aDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4 1 T cells were maintained, resulting in improved survival. Conventional T cells derived from aDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNg, IL-1b, and TNFa) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from aDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of aDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. (Blood. 2015; 126(4):546-557)

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“…5A, CCR9 ϩ T cells isolated from CD LPL secrete significantly more IFN-␥ compared with CCR9 ϩ T cells isolated from normal LPL when activated with anti-CD3 plus anti-CD28 Abs or with the cytokines IL-12 and IL-18. Interestingly, the addition of TL1A, which was recently shown to synergize with IL-12 and IL-18 to enhance IFN-␥ production by CCR9 ϩ PB and LP T cells (13), significantly enhanced the secretion of IFN-␥ by CCR9 ϩ T cells isolated from inflamed CD SB compared with CCR9 ϩ T cells isolated from normal SB (Fig. 5A).…”

Section: Ccr9 ϩ T Cells Isolated From Inflamed Sb Have a Th1 And Thilmentioning

confidence: 88%

“…We reported previously that TL1A, a newly discovered cytokine, synergizes with IL-12 and IL-18 to enhance IFN-␥ in human T cells, and particularly in PB and SB CCR9 ϩ T cells (13,17). In this study, we also demonstrate that addition of TL1A to IL-12/ IL-18 cytokine combination markedly enhanced secretion of IFN-␥ by CCR9 ϩ T cells from inflamed CD SB, indicating an important role of TL1A/DR3 interactions in enhancing Th1 immune responses in CD from cytokine stimulated CCR9 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Chemokines constitute a large family of small (ϳ8 -14 kDa), structurally related heparin binding proteins, which are constitutively expressed in lymphoid and extra lymphoid tissues, and play a critical role in immune homeostasis by regulating lymphocyte trafficking to or within lymphoid organs and in peripheral tissues (7)(8)(9)(10)(11)(12)(13). They are classified as C, CC, CXC, and CX3C based on the positioning of cysteine residues that form two disulfide bonds (14).…”

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confidence: 99%

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Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Saruta¹,

Yu²,

Avanesyan³

et al. 2007

The Journal of Immunology

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CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn’s disease (CD) and an increased frequency of CCR9+ T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9+ T cells in mucosal lymphoid tissues in CD. We show that CCR9+ T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9+ T cells isolated from CD SB lamina propria produced more IFN-γ and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-γ, but not IL-17, by CD lamina propria CCR9+ T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVβ analysis of CCR9+ T cells revealed a diverse TCRVβ repertoire among MLN CCR9+ T cells in patients with SB CD. Our data indicate that CCR9+ T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.

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Dominant Role for TL1A/DR3 Pathway in IL-12 plus IL-18-Induced IFN-γ Production by Peripheral Blood and Mucosal CCR9+ T Lymphocytes

Cited by 109 publications

References 28 publications

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

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