Immunology Institute

New York City, NY, United States

Immunology Institute

New York City, NY, United States
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Merad M.,Immunology Institute | Merad M.,Tisch Cancer Institute | Sathe P.,Immunology Institute | Helft J.,Immunology Institute | And 2 more authors.
Annual Review of Immunology | Year: 2013

Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ. © Copyright 2013 by Annual Reviews. All rights reserved.

McNerney G.P.,National Science Foundation | Huner W.,Immunology Institute | Chen B.K.,Immunology Institute | Huser T.,National Science Foundation | Huser T.,University of California at Davis
Journal of Biophotonics | Year: 2010

Cell-cell interactions through direct contact are very important for cellular communication and coordination-especially for immune cells. The human immunodeficiency virus type I (HIV-1) induces immune cell interactions between CD4+ cells to shuttle between T cells via a virological synapse. A goal to understand the process of cell-cell transmission through virological synapses is to determine the cellular states that allow a chance encounter between cells to become a stable cell-cell adhesion. We demonstrate the use of optical tweezers to manipulate uninfected primary CD4+ T cells near HIV Gag-iGFP transfected Jurkat T cells to probe the determinants that induce stable adhesion. When combined with fast 4D confocal fluorescence microscopy, optical tweezers can be utilized not only to facilitate cell-cell contact, but also to simultaneously track the formation of a virological synapse, and ultimately to probe the events that precede virus transfer. HIV-1 infected T cell (green) decorated with uninfected primary T cells (red) by manipulating the primary cells with an optical tweezers system. © 2010 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Menard L.,Yale University | Cantaert T.,Yale University | Chamberlain N.,Yale University | Tangye S.G.,University of New South Wales | And 6 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) can mediate the function of SLAM molecules, which have been proposed to be involved in the development of autoimmunity in mice. Objective We sought to determine whether the SLAM/SAP pathway regulates the establishment of human B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP deficiency. Methods We tested the reactivity of antibodies isolated from single B cells from SAP-deficient patients with X-linked lymphoproliferative disease (XLP). The expressions of SAP and SLAM family members were assessed in human bone marrow-developing B cells. We also analyzed regulatory T (Treg) cell function in patients with XLP and healthy control subjects. Results We found that new emigrant/transitional B cells from patients with XLP were enriched in autoreactive clones, revealing a defective central B-cell tolerance checkpoint in the absence of functional SAP. In agreement with a B cell-intrinsic regulation of central tolerance, we identified SAP expression in a discrete subset of bone marrow immature B cells. SAP colocalized with SLAMF6 only in association with clustered B-cell receptors likely recognizing self-antigens, suggesting that SLAM/SAP regulate B-cell receptor-mediated central tolerance. In addition, patients with XLP displayed defective peripheral B-cell tolerance, which is normally controlled by Treg cells. Treg cells in patients with XLP seem functional, but SAP-deficient T cells were resistant to Treg cell-mediated suppression. Indeed, SAP-deficient T cells were hyperresponsive to T-cell receptor stimulation, which resulted in increased secretion of IL-2, IFN-γ, and TNF-α. Conclusions SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T cell-dependent accumulation in the periphery. © 2013 American Academy of Allergy, Asthma & Immunology.

Shulzhenko N.,U.S. National Institutes of Health | Shulzhenko N.,Oregon State University | Morgun A.,U.S. National Institutes of Health | Morgun A.,Oregon State University | And 11 more authors.
Nature Medicine | Year: 2011

Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.

Van Der Touw W.,Mount Sinai School of Medicine | Burrell B.,Mount Sinai School of Medicine | Lal G.,Mount Sinai School of Medicine | Bromberg J.S.,Mount Sinai School of Medicine | And 2 more authors.
Transplantation | Year: 2012

BACKGROUND: The role of natural killer (NK) cells in organ transplantation is poorly understood because studies link these cells to both regulatory and inflammatory functions. NK cells exacerbate inflammation and adaptive immunity under conditions of allograft rejection, but little is known regarding their roles in allograft tolerance. We test the hypothesis that NK cells have regulatory function and promote tolerance induction to murine cardiac allografts. METHODS: Murine hearts were transplanted as fully vascularized heterotopic grafts from BALB/c donors into C57BL/6 recipients. Allograft tolerance was achieved using donor splenocyte transfusion + anti-CD40L monoclonal antibody (mAb) before transplantation. The requirement for NK cells in tolerance induction was tested by administering anti-NK1.1-depleting mAb or anti-NKG2D-blocking mAb. Intragraft and peripheral immune cell populations were determined by flow cytometry and immunohistochemistry. CD4 T-cell alloantigen-specific responses and donor-specific alloantibody were also determined. RESULTS: NK cell-depleted recipients acutely reject allografts despite anti-CD40L blockade, but rejecting recipients lacked alloantibody and alloantigen-specific CD4 T-cell responses. NK cell depletion resulted in elevated numbers of graft-infiltrating macrophages. NKG2D blockade in tolerized recipients did not cause acute rejection but increased macrophage graft infiltration and increased the expression of NKG2D ligand Rae-1γ on these cells. CONCLUSIONS: Our data show that NK cells are required for tolerance induction in recipients given donor splenocyte transfusion + anti-CD40L mAb. Our data suggest NK cells regulate monocyte or macrophage activation and infiltration into allografts by a mechanism partially dependent on NKG2D receptor-ligand interactions between NK cells and monocytes/macrophages. Copyright © 2012 by Lippincott Williams & Wilkins.

Mayer L.,Immunology Institute
Journal of Gastroenterology | Year: 2010

The pathogenesis of all immune-mediated inflammatory diseases has been carefully studied over the past several decades, but it is only recently that we have come to appreciate common pathways and genes. This is especially true for the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, where a keener appreciation of the contributions of genetics, environment, and immune response have been dissected. In fact, in many ways, IBD has become the model for studying such disorders. The complex nature of interactions is continuing to be defined, and novel therapies targeting defects in these interactions have been developed and are being tested in the clinic. The era of bench to bedside has finally matured, and cures for debilitating diseases are now in sight. This review describes our current state of knowledge of each component of IBD pathogenesis. What has evolved is a clearer picture and novel targets for therapy. © 2009 Springer.

Heymann F.,RWTH Aachen | Hammerich L.,RWTH Aachen | Storch D.,RWTH Aachen | Bartneck M.,RWTH Aachen | And 7 more authors.
Hepatology | Year: 2012

Chemokines critically control the infiltration of immune cells upon liver injury, thereby promoting hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte-derived dendritic cells (DCs) and T-helper cell (Th) subsets, but its role in liver diseases is currently unknown. To investigate the functional role of CCR8 in liver diseases, ccr8 -/- and wild-type (WT) mice were subjected to chronic experimental injury models of carbon tetrachloride (CCl 4) administration and surgical bile duct ligation (BDL). CCR8 was strongly up-regulated in the injured liver. Ccr8 -/- mice displayed attenuated liver damage (e.g., ALT, histology, and TUNEL) compared to WT mice and were also protected from liver fibrosis in two independent injury models. Flow cytometry revealed reduced infiltrates of liver macrophages, neutrophils and natural killer cells, whereas hepatic CD4 + T cells increased. The main CCR8-expressing cells in the liver were hepatic macrophages, and CCR8 was functionally necessary for CCL1-directed migration of inflammatory but not for nonclassical monocytes into the liver. Moreover, the phenotype of liver macrophages from injured ccr8 -/- animals was altered with increased expression of DC markers and enhanced expression of T-cell-attracting chemokine macrophage inflammatory protein 1-alpha (MIP-1α/CCL3). Correspondingly, hepatic CD4 + T cells showed increased Th1 polarization and reduced Th2 cells in CCR8-deficient animals. Liver fibrosis progression, but also subsequent T-cell alterations, could be restored by adoptively transferring CCR8-expressing monocytes/macrophages into ccr8 -/- mice during experimental injury. Conclusions: CCR8 critically mediates hepatic macrophage recruitment upon injury, which subsequently shapes the inflammatory response in the injured liver, affecting macrophage/DC and Th differentiation. CCR8 deficiency protects the liver against injury, ameliorating initial inflammatory responses and hepatic fibrogenesis. Inhibition of CCR8 or its ligand, CCL1, might represent a successful therapeutic target to limit liver inflammation and fibrosis progression. (Hepatology 2012) © 2011 American Association for the Study of Liver Diseases.

Yang W.-C.,Immunology Institute | Ma G.,Immunology Institute | Chen S.-H.,Immunology Institute | Pan P.-Y.,Immunology Institute
Journal of Molecular Cell Biology | Year: 2013

Myeloid-derived suppressor cells (MDSC) have recently emerged as one of the central regulators of the immune system. In recent years, interest in understanding MDSC biology and applying MDSC for therapeutic purpose has exploded exponentially. Despite recent progress in MDSC biology, the mechanisms underlying MDSC development from expansion and activation to polarization in different diseases remain poorly understood. More recent studies have demonstrated that two MDSC subsets, M (monocytic)-MDSC and G (granulocytic)-MDSC, are able to polarize from a classically activated phenotype (M1) to an alternatively activated one (M2), or vice versa, in tumor-bearing mice. This phenotypic polarization affects MDSC function and disease progression. In this article, we summarize and discuss polarization, mechanism and therapeutic potential of MDSC. An emphasis is placed on the emerging concept of reprogramming MDSC polarization as a therapeutic strategy. © 2013 © The Author (2013). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Hammerich L.,RWTH Aachen | Bangen J.M.,RWTH Aachen | Govaere O.,Catholic University of Leuven | Zimmermann H.W.,RWTH Aachen | And 10 more authors.
Hepatology | Year: 2014

Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis. We hypothesized a contribution of chemokine receptor CCR6 and its ligand, CCL20, which may regulate migration of T-helper (Th)17, regulatory, and gamma-delta (γδ) T cells. CCR6 and CCL20 expression was intrahepatically up-regulated in patients with chronic liver diseases (n = 50), compared to control liver (n = 5). Immunohistochemistry revealed the periportal accumulation of CCR6+ mononuclear cells and CCL20 induction by hepatic parenchymal cells in liver disease patients. Similarly, in murine livers, CCR6 was expressed by macrophages, CD4 and γδ T-cells, and up-regulated in fibrosis, whereas primary hepatocytes induced CCL20 upon experimental injury. In two murine models of chronic liver injury (CCl4 and methionine-choline-deficient diet), Ccr6-/- mice developed more severe fibrosis with strongly enhanced hepatic immune cell infiltration, compared to wild-type (WT) mice. Although CCR6 did not affect hepatic Th-cell subtype composition, CCR6 was explicitly required by the subset of interleukin (IL)-17- and IL-22-expressing γδ T cells for accumulation in injured liver. The adoptive transfer of WT γδ, but not CD4 T cells, into Ccr6-/- mice reduced hepatic inflammation and fibrosis in chronic injury to WT level. The anti-inflammatory function of hepatic γδ T cells was independent of IL-17, as evidenced by transfer of Il-17-/- cells. Instead, hepatic γδ T cells colocalized with hepatic stellate cells (HSCs) in vivo and promoted apoptosis of primary murine HSCs in a cell-cell contact-dependent manner, involving Fas-ligand (CD95L). Consistent with γδ T-cell-induced HSC apoptosis, activated myofibroblasts were more frequent in fibrotic livers of Ccr6-/- than in WT mice. Conclusion: γδ T cells are recruited to the liver by CCR6 upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSCs. © 2013 by the American Association for the Study of Liver Diseases.

Berres M.-L.,Mount Sinai School of Medicine | Berres M.-L.,Tisch Cancer Institute | Berres M.-L.,Immunology Institute | Allen C.E.,Texas Childrens Cancer Center | And 4 more authors.
Advances in Immunology | Year: 2013

Histiocytic disorders represent a group of complex pathologies characterized by the accumulation of histiocytes, an old term for tissue-resident macrophages and dendritic cells. Langerhans cell histiocytosis is the most frequent of histiocytosis in humans and has been thought to arise from the abnormal accumulation of epidermal dendritic cells called Langerhans cells. In this chapter, we discuss the origin and differentiation of Langerhans cells and dendritic cells and present accumulated evidence that suggests that Langerhans cell histiocytosis does not result from abnormal Langerhans cell homeostasis but rather is a consequence of misguided differentiation programs of myeloid dendritic cell precursors. We propose reclassification of Langerhans cell histiocytosis, juvenile xanthogranuloma, and Erdheim-Chester disease as inflammatory myeloid neoplasias. © 2013 Elsevier Inc.

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