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Immunology

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IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis
Youjin Lee, … , Raymond A. Sobel, Vijay K. Kuchroo
Youjin Lee, … , Raymond A. Sobel, Vijay K. Kuchroo
Published September 28, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI75933.
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IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis

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Abstract

IL-17–producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21–mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.

Authors

Youjin Lee, Meike Mitsdoerffer, Sheng Xiao, Guangxiang Gu, Raymond A. Sobel, Vijay K. Kuchroo

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TIGIT predominantly regulates the immune response via regulatory T cells
Sema Kurtulus, … , Vijay K. Kuchroo, Ana C. Anderson
Sema Kurtulus, … , Vijay K. Kuchroo, Ana C. Anderson
Published September 28, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI81187.
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TIGIT predominantly regulates the immune response via regulatory T cells

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Abstract

Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.

Authors

Sema Kurtulus, Kaori Sakuishi, Shin-Foong Ngiow, Nicole Joller, Dewar J. Tan, Michele W.L. Teng, Mark J. Smyth, Vijay K. Kuchroo, Ana C. Anderson

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Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells
Taeg S. Kim, … , Paul C. Trampont, Thomas J. Braciale
Taeg S. Kim, … , Paul C. Trampont, Thomas J. Braciale
Published September 21, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI81919.
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Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells

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Abstract

Erythropoiesis is an important response to certain types of stress, including hypoxia, hemorrhage, bone marrow suppression, and anemia, that result in inadequate tissue oxygenation. This stress-induced erythropoiesis is distinct from basal red blood cell generation; however, neither the cellular nor the molecular factors that regulate this process are fully understood. Here, we report that type 1 conventional dendritic cells (cDC1s), which are defined by expression of CD8α in the mouse and XCR1 and CLEC9 in humans, are critical for induction of erythropoiesis in response to stress. Specifically, using murine models, we determined that engagement of a stress sensor, CD24, on cDC1s upregulates expression of the Kit ligand stem cell factor on these cells. The increased expression of stem cell factor resulted in Kit-mediated proliferative expansion of early erythroid progenitors and, ultimately, transient reticulocytosis in the circulation. Moreover, this stress response was triggered in part by alarmin recognition and was blunted in CD24 sensor– and CD8α+ DC-deficient animals. The contribution of the cDC1 subset to the initiation of stress erythropoiesis was distinct from the well-recognized role of macrophages in supporting late erythroid maturation. Together, these findings offer insight into the mechanism of stress erythropoiesis and into disorders of erythrocyte generation associated with stress.

Authors

Taeg S. Kim, Mark Hanak, Paul C. Trampont, Thomas J. Braciale

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Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Published September 14, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI79271.
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Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

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Abstract

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.

Authors

Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky

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Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients
Francesca Pala, … , Anna Villa, Eric Meffre
Francesca Pala, … , Anna Villa, Eric Meffre
Published September 14, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI82249.
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Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

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Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients.

Authors

Francesca Pala, Henner Morbach, Maria Carmina Castiello, Jean-Nicolas Schickel, Samantha Scaramuzza, Nicolas Chamberlain, Barbara Cassani, Salome Glauzy, Neil Romberg, Fabio Candotti, Alessandro Aiuti, Marita Bosticardo, Anna Villa, Eric Meffre

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Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease
Holly A. Bolton, … , Elena Shklovskaya, Barbara Fazekas de St. Groth
Holly A. Bolton, … , Elena Shklovskaya, Barbara Fazekas de St. Groth
Published August 24, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI76031.
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Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

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Abstract

Regulatory T cells (Tregs) have been shown to enhance immune reconstitution and prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation; however, it is unclear how Tregs mediate these effects. Here, we developed a model to examine the mechanism of Treg-dependent regulation of immune reconstitution. Lymphopenic mice were selectively reconstituted with Tregs prior to transfer of conventional CD4+ T cells. Full Treg reconstitution prevented the rapid oligoclonal proliferation that gives rise to pathogenic CD4 effector T cells, while preserving the slow homeostatic form of lymphopenia-induced peripheral expansion that repopulates a diverse peripheral T cell pool. Treg-mediated CTLA-4–dependent downregulation of CD80/CD86 on DCs was critical for inhibition of rapid proliferation and was a function of the Treg/DC ratio achieved by reconstitution. In an allogeneic BM transplant model, selective Treg reconstitution before T cell transfer also normalized DC costimulation and provided complete protection against GVHD. In contrast, cotransfer of Tregs was not protective. Our results indicate that achieving optimal recovery from lymphopenia should aim to improve early Treg reconstitution in order to increase the relative number of Tregs to DCs and thereby inhibit spontaneous oligoclonal T cell proliferation.

Authors

Holly A. Bolton, Erhua Zhu, Alexandra M. Terry, Thomas V. Guy, Woon-Puay Koh, Sioh-Yang Tan, Carl A. Power, Patrick Bertolino, Katharina Lahl, Tim Sparwasser, Elena Shklovskaya, Barbara Fazekas de St. Groth

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Inflammatory IL-15 is required for optimal memory T cell responses
Martin J. Richer, … , Steven M. Varga, John T. Harty
Martin J. Richer, … , Steven M. Varga, John T. Harty
Published August 4, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI81261.
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Inflammatory IL-15 is required for optimal memory T cell responses

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Abstract

Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection. Using murine models of viral infection and antigen exposure, we found that type I IFN–driven expression of IL-15 in response to viral infection prepares memory CD8+ T cells for rapid division independently of antigen reexposure by transiently inducing cell-cycle progression via a pathway dependent on mTOR complex-1 (mTORC1). Moreover, exposure to IL-15 allowed more rapid division of memory CD8+ T cells following antigen encounter and enhanced their protective capacity against viral infection. Together, these data reveal that inflammatory IL-15 promotes optimal responses by memory CD8+ T cells.

Authors

Martin J. Richer, Lecia L. Pewe, Lisa S. Hancox, Stacey M. Hartwig, Steven M. Varga, John T. Harty

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Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease
Neil E. McCarthy, … , James O. Lindsay, Andrew J. Stagg
Neil E. McCarthy, … , James O. Lindsay, Andrew J. Stagg
Published July 13, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI80840.
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Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

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Abstract

Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a Vγ9Vδ2 T cell receptor (Vδ2 T cells) and mediate host protection against microbial infections and malignancies. Vδ2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed Vδ2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn’s disease patients (CD patients) and healthy controls. Blood from CD patients included an increased percentage of gut-tropic integrin β7–expressing Vδ2 T cells, while “Th1-committed” CD27-expressing Vδ2 T cells were selectively depleted. A corresponding population of CD27+ Vδ2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNFα compared with controls. In colonic mucosa from CD patients, Vδ2 T cell production of TNFα was reduced by pharmacological blockade of retinoic acid receptor-α (RARα) signaling, indicating that dietary vitamin metabolites can influence Vδ2 T cell function in inflamed intestine. Vδ2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment Vδ2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human Vδ2 T cells exert proinflammatory effects in CD that are modified by dietary vitamin metabolites and ablated by AZA therapy, which may help resolve intestinal inflammation but could increase malignancy risk by impairing systemic tumor surveillance.

Authors

Neil E. McCarthy, Charlotte R. Hedin, Theodore J. Sanders, Protima Amon, Inva Hoti, Ibrahim Ayada, Vidya Baji, Edward M. Giles, Martha Wildemann, Zora Bashir, Kevin Whelan, Ian Sanderson, James O. Lindsay, Andrew J. Stagg

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Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus
Hao Li, … , Hui-Chen Hsu, John D. Mountz
Hao Li, … , Hui-Chen Hsu, John D. Mountz
Published June 22, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI81059.
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Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus

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Abstract

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is associated with increased circulating apoptotic cell autoantigens (AC-Ags) as well as increased type I IFN signaling. Here, we describe a pathogenic mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleens of BXD2 lupus mice disrupts marginal zone macrophages (MZMs), which normally clear AC debris and prevent follicular entry of AC-Ags. Phagocytosis of ACs by splenic MZMs required the megakaryoblastic leukemia 1 (MKL1) transcriptional coactivator–mediated mechanosensing pathway, which was maintained by MZ B cells through expression of membrane lymphotoxin-α1β2 (mLT). Specifically, type I IFN–induced follicular shuttling of mLT-expressing MZ B cells disengaged interactions between these MZ B cells and LTβ receptor–expressing MZMs, thereby downregulating MKL1 in MZMs. Loss of MKL1 expression in MZMs led to defective F-actin polymerization, inability to clear ACs, and, eventually, MZM dissipation. Aggregation of plasmacytoid DCs in the splenic perifollicular region, follicular translocation of MZ B cells, and loss of MKL1 and MZMs were also observed in an additional murine lupus model and in the spleens of patients with SLE. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signaling in the MZM barrier to prevent follicular entry of AC-Ags.

Authors

Hao Li, Yang-Xin Fu, Qi Wu, Yong Zhou, David K. Crossman, PingAr Yang, Jun Li, Bao Luo, Laurence M. Morel, Janusz H. Kabarowski, Hideo Yagita, Carl F. Ware, Hui-Chen Hsu, John D. Mountz

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Mature T cell responses are controlled by microRNA-142
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Published June 22, 2015
Citation Information: J Clin Invest. 2015. https://doi.org/10.1172/JCI78753.
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Mature T cell responses are controlled by microRNA-142

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Abstract

T cell proliferation is critical for immune responses; however, the molecular mechanisms that mediate the proliferative response are poorly understood. MicroRNAs (miRs) regulate various molecular processes, including development and function of the immune system. Here, utilizing multiple complementary genetic and molecular approaches, we investigated the contribution of a hematopoietic-specific miR, miR-142, in regulating T cell responses. T cell development was not affected in animals with a targeted deletion of Mir142; however, T cell proliferation was markedly reduced following stimulation both in vitro and in multiple murine models of graft-versus-host disease (GVHD). miR-142–deficient T cells demonstrated substantial cell-cycling defects, and microarray and bioinformatics analyses revealed upregulation of genes involved in cell cycling. Moreover, 2 predicted miR-142 target genes, the atypical E2F transcription factors E2f7 and E2f8, were most highly upregulated in miR-142–deficient cells. Clustered regularly interspaced short palindromic repeat interference–mediated (CRISPRi-mediated) silencing of E2F7 and E2F8 in miR-142–deficient T cells ameliorated cell-cycling defects and reduced GVHD, and overexpression of these factors in WT T cells inhibited the proliferative response. Together, these results identify a link between hematopoietic-specific miR-142 and atypical E2F transcription factors in the regulation of mature T cell cycling and suggest that targeting this interaction may be relevant for mitigating GVHD.

Authors

Yaping Sun, Katherine Oravecz-Wilson, Nathan Mathewson, Ying Wang, Richard McEachin, Chen Liu, Tomomi Toubai, Julia Wu, Corinne Rossi, Thomas Braun, Thomas Saunders, Pavan Reddy

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