Dll4–Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice

Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 04/2012; 209(5):1011-28. DOI: 10.1084/jem.20111615
Source: PubMed


Delta-like ligand 4 (Dll4)-Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4-Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg) cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural T(reg) cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4(-)CD8(-)c-kit(+)CD44(+)CD25(-) (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4(+) T cells into T(reg) cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of T(reg) cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti-Dll4 treatment fully prevents type 1 diabetes (T1D) via a T(reg) cell-mediated mechanism and inhibits CD8(+) T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased T(reg) cell numbers in the pancreas-draining lymph nodes. These results identify Dll4-Notch as a novel Flt3-alternative pathway important for regulating tDC-mediated T(reg) cell homeostasis and autoimmunity.

Download full-text


Available from: Guillaume Darrasse-Jeze
  • Source
    • "Ligand proteins binding to the EGF domains induce proteolytic cleavage and release of the intracellular domain, which enters the cell nucleus to modify gene expression [119]. Interaction between Notch receptors and their ligands represents an evolutionarily conserved signaling pathway important for cell fate commitment in hematopoiesis and thymus development [120–122]. A new addition to the Delta family of Notch ligands, named Delta-like ligand 4 (Dll4), is predicted to encode a membrane-bound ligand. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this review, we explore the role of dendritic cell subsets in the development of tissue-specific autoimmune diseases. From the increasing list of dendritic cell subclasses, it is becoming clear that we are only at the beginning of understanding the role of these antigen presenting cells in mediating autoimmunity. Emerging research areas for the study of dendritic cell involvement in the onset and inhibition of tissue-specific autoimmunity are presented. Further, we compare tissue specific to systemic autoimmunity to demonstrate how development of dendritic cell-based therapies may be broadly applicable to both classes of autoimmunity. Continued development of these research areas will lead us closer to clinical assessment of novel immunosuppressive therapy for the reversal and prevention of tissue-specific autoimmunity. Through description of dendritic cell functions in the modulation of tissue-specific autoimmunity, we hope to stimulate a greater appreciation and understanding of the role dendritic cells play in the development and treatment of autoimmunity.
    Full-text · Article · Apr 2014 · Research Journal of Immunology
  • Source
    • "Bassil et al. show that Dll4 mediated signaling inhibits TGF-β-induced Treg development as well as Janus kinase 3-induced STAT5 phosphorylation, a transcription factor known to play a key role in Foxp3 expression and maintenance [13]. The role of Dll4 in Treg development was further confirmed by Billiard et al. by showing that anti-Dll4 Ab treatment converts early T cell progenitors to immature tolerogenic DCs that promote Treg-cell expansion [14]. Adding another dimension to the picture, Hue et al. demonstrate that pretreatment with Notch ligands Dll4 and Jagged1 sensitizes CD4+CD25− effector T cells to Treg-cell mediated suppression through increased TGF-βRII expression and Smad3 phosphorylation [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Notch signaling pathway preservation across species hints to the indispensable role it plays during evolution. Over the last decade the science community has extensively studied the Notch signaling pathway, with Notch emerging as a key player in embryogenesis, tissue homeostasis, angiogenesis, and immunoregulation. Multiple sclerosis (MS) is an incurable yet treatable autoimmune chronic inflammatory disease of the central nervous system. The aim of this review is to provide a brief description of the Notch signaling pathway, and summarize the current literature implicating Notch in the pathogenesis of MS.
    Full-text · Article · Nov 2013 · Clinical and Developmental Immunology
  • Source
    • "In this paper, the Sheppard team showed that DCs lacking the TGF-β-activating integrin αvβ8 failed to induce Tregs in vitro, and that mice with conditional deletion of αvβ8 in DCs presented reduced proportions of Treg cells in colonic tissue. If It should not be excluded that effector cell expansion may contributes to this observed reduction in the fractional number of Treg cells in the colon, these in vitro and in vivo results reinforce observations that DCs are essential in the maintenance of both pTreg and tTreg cells in the periphery (82–85). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The influence of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) on cancer progression has been demonstrated in a large number of preclinical models and confirmed in several types of malignancies. Neoplastic processes trigger an increase of Treg numbers in draining lymph nodes, spleen, blood, and tumors, leading to the suppression of anti-tumor responses. Treg-depletion before or early in tumor development may lead to complete tumor eradication and extends survival of mice and humans. However this strategy is ineffective in established tumors, highlighting the critical role of the early Treg-tumor encounters. In this review, after discussing old and new concepts of immunological tumor tolerance, we focus on the nature (thymus-derived vs. peripherally derived) and status (naïve or activated/memory) of the regulatory T-cells at tumor emergence. The recent discoveries in this field suggest that the activation status of Tregs and effector T-cells (Teffs) at the first encounter with the tumor are essential to shape the fate and speed of the immune response across a variety of tumor models. The relative timing of activation/recruitment of anti-tumor cells vs. tolerogenic cells at tumor emergence appears to be crucial in the identification of tumor cells as friend or foe, which has broad implications for the design of cancer immunotherapies.
    Full-text · Article · Sep 2013 · Frontiers in Immunology
Show more