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Chatila, Talal

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Chatila

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Talal

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Chatila, Talal
Author's Publications: search.filters.isAuthorOfPublication.530a7858-96dc-47d4-a6a4-bb8fc979fd08

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Now showing 1 - 5 of 5
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    Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases
    (F1000 Research Limited, 2018) Abdel-Gadir, Azza; Massoud, Amir H.; Chatila, Talal
    Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.
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    WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis
    (Nature Publishing Group UK, 2018) Biswas, Amlan; Shouval, Dror S.; Griffith, Alexandra; Goettel, Jeremy; Field, Michael; Kang, Yu Hui; Konnikova, Liza; Janssen, Erin; Redhu, Naresh; Thrasher, Adrian J.; Chatila, Talal; Kuchroo, Vijay; Geha, Raif; Notarangelo, Luigi D.; Pai, Sung-Yun; Horwitz, Bruce; Snapper, Scott
    Mutations in Wiskott–Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.
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    Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling
    (2015) Charbonnier, Louis-Marie; Wang, Sen; Georgiev, Peter; Sefik, Esen; Chatila, Talal
    Notch receptors direct the differentiation of T helper (TH) cell subsets, but their influence on regulatory T (Treg) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced Treg cell-mediated suppression of TH1 responses, and protected against their TH1 skewing and apoptosis. Expression in Treg cells of gain of function transgene encoding Notch1 intracellular domain resulted in lymphoproliferation, exacerbated TH1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired Treg cell fitness, promoted the acquisition by Treg cells of a TH1 cell-like phenotype, whereas Rictor-dependent non-canonical Notch signaling activated the AKT-Foxo1 axis and impaired Foxp3 epigenetic stability. These findings establish a critical role for Notch signaling in controlling peripheral Treg cell functions.
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    An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells
    (2016) Massoud, Amir Hossein; Charbonnier, Louis-Marie; Lopez, David; Pellegrini, Matteo; Phipatanakul, Wanda; Chatila, Talal
    Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL4RA R576) promotes conversion of induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα-R576 of the growth factor receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway involving extracellular signal-regulated kinase, IL-6 and STAT3. Treg cell-specific deletion of Il6ra or Rorc, but not Il4 or Il13, prevented exacerbated airway inflammation in Il4raR576 mice. Furthermore, treatment of Il4raR576 mice with a neutralizing anti-IL-6 antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a novel mechanism for the development of mixed TH2-TH17 cell inflammation in genetically prone individuals, and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.
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    DOCK8 Functions as an Adaptor that Links TLR–MyD88 Signaling to B Cell Activation
    (Nature Publishing Group, 2012) Rauter, Ingrid; Recher, Mike; Wakim, Rima; Dbaibo, Ghassan; Dasouki, Majed; Barlan, Isil; Baris, Safa; Kutukculer, Necil; Ochs, Hans; Plebani, Alessandro; Kanariou, Maria; Lefranc, Gerard; Reisli, Ismail; Fitzgerald, Katerine; Golenbock, Douglas; Keles, Sevgi; Ceja, Reuben; Jabara, Haifa Halim; McDonald, Douglas; Janssen, Erin; Massaad, Michel; Ramesh, Narayanaswamy; Borzutzky, Arturo; Benson, Halli Louise; Schneider, Lynda; Baxi, Sachin; Notarangelo, Luigi; Al-Herz, Waleed; Manis, John; Chatila, Talal; Geha, Raif
    DOCK8 and MyD88 have been implicated in serologic memory. Here we report antibody responses were impaired and \(CD27^+\) memory B cells were severely reduced in DOCK8-deficient patients. Toll-like receptor 9 (TLR9)- but not CD40-driven B cell proliferation and immunoglobulin production were severely reduced in DOCK8-deficient B cells. In contrast, TLR9-driven expression of AICDA, CD23 and CD86, and activation of NF-κB, p38 and Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. Following TLR9 ligation, DOCK8 became tyrosine phosphorylated by Pyk2, bound the Src family kinase Lyn and linked TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.