DOCSLIB.ORG

IL-1 Receptor Antagonist-Deficient Mice Develop Autoimmune Arthritis Due

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IL-1 Receptor Antagonist-Deficient Mice Develop Autoimmune Arthritis Due ARTICLE Received 24 Jan 2015 | Accepted 13 May 2015 | Published 25 Jun 2015 DOI: 10.1038/ncomms8464 OPEN IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2 þ Vg6 þ gd T cells Aoi Akitsu1,2,3,4,5, Harumichi Ishigame1,w, Shigeru Kakuta1,w, Soo-hyun Chung1,5, Satoshi Ikeda1, Kenji Shimizu1,5, Sachiko Kubo1,5, Yang Liu1,w, Masayuki Umemura6, Goro Matsuzaki6, Yasunobu Yoshikai7, Shinobu Saijo1,w & Yoichiro Iwakura1,2,4,5 Interleukin-17 (IL-17)-producing gd T(gd17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4 þ and gd17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4 þ T cells direct gd T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vg6 þ subset of CCR2 þ gd T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on gd T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vg6 þ cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner. 1 Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 2 Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan. 3 Research Fellow of the Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan. 4 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan. 5 Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan. 6 Tropical Biosphere Research Center, University of the Ryukyus, Okinawa 903-0213, Japan. 7 Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. w Present addresses: RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan (H.I.); Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan (S.K.); Renji Hospital Clinical Stem Cell Research Center, Shanghai Jiao Tong University School of Medicine, Shang Hai 200127, China (Y.L.); Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 263-8522, Japan (S.S.). Correspondence and requests for materials should be addressed to Y.I. (email: [email protected]). NATURE COMMUNICATIONS | 6:7464 | DOI: 10.1038/ncomms8464 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8464 nterleukin (IL)-17 plays important roles in the development of development of arthritis. Both Vg6 þ and Vg4 þ gd T cells autoimmune diseases, such as rheumatoid arthritis and were recruited to the joints, but only the Vg6 þ subset efficiently Ipsoriasis, by inducing expression of proinflammatory cyto- produced IL-17, because Il1rn À / À Vg6 þ cells intrinsically kines and chemokines, recruiting neutrophils and activating expressed high levels of IL-1R due to the loss of down- T cells and B cells1,2. Although helper CD4 þ T (Th17) cells regulation of IL-1R expression by IL-1Ra. These observations are well-known producers of IL-17 that contribute to the provide novel insights into the pathogenic mechanism underlying development of autoimmune diseases, recent studies showed the development of autoimmune arthritis in Il1rn À / À mice. that innate immune cells and innate-like cells are also important 3,4 sources of IL-17 in local inflammatory tissues . Mouse Results autoimmune disease models have revealed that IL-17-producing cd T cells mainly produce IL-17 in Il1rn À / À mouse joints.We gd T(gd17) cells are an important innate source of IL-17 analysed IL-17-producing cells in arthritic Il1rn À / À mice. Both (refs 5–13). In collagen-induced arthritis, experimental auto- gd17 cell and Th17 cell populations were elevated in draining immune encephalomyelitis and psoriasis-like skin inflammation, lymph nodes (LNs) of affected joints (Fig. 1a,b), whereas pro- the synergy between gd17 and ab T cells is important for disease þ þ þ þ 5,6,11,14 portions of IL-17 CD8 T cells and IL-17 DX5 T cells were development , but it remains unclear how gd17 cells induce unchanged (Supplementary Fig. 1). Notably, most joint-infiltrat- tissue-specific inflammation. ing IL-17-producing cells were gd T cells, whereas Th17 cells were gd17 cells share many characteristics with Th17 cells. However, rare (Fig. 1c). Moreover, immunofluorescence staining revealed in contrast to Th17 cells in which differentiation in the periphery that IL-17 in the joints was primarily expressed in gd T cells is required for IL-17 production, the functional potential of gd17 gd 15–17 (Fig. 1d). These observations suggest that 17 cells play a cells is already determined during intrathymic development . pathogenic role in the development of arthritis in Il1rn À / À mice. These gd thymocytes, which express the transcription factor 18 RORgt and the signature cytokine receptor IL-23R , leave the þ thymus as functionally committed cells19. Therefore, gd T cells cd and CD4 T cells are involved in arthritis development.To analyse the pathogenic roles of gd T cells and CD4 þ T cells, we produce IL-17 directly following stimulation with IL-1b and IL- À / À 23 without T cell receptor (TCR) stimulation in the periphery5,13. injected either anti-gd TCR or anti-CD4 mAb into Il1rn Although the expression of IL-23R on gd17 cells is constitutive5, mice before onset of disease. Both antibody treatments sig- expression of IL-1R in the periphery is tissue-type dependent20. nificantly suppressed the incidence of arthritis (Fig. 2a,b). Il1r1 À / À mice or anti-IL-1R monoclonal antibody (mAb) Although the severity scores, determined by the swelling and treatment abrogates IL-17 production in gd T cells11,20, ankylosing changes of the affected ankles of antibody-treated suggesting that IL-1R expression plays a critical role in IL-17 mice, were similar to those of untreated mice (Supplementary production. However, the regulatory mechanism of IL-1R Fig. 2a,b), the microscopic histological scores significantly expression remains unclear. In addition to RORgt, transcription decreased following treatment with anti-gd TCR mAb (Fig. 2c,d). factors such as Blk21, Hes-1 (ref. 22), NFkB23, SOX4 and SOX13 Anti-gd TCR mAb treatment depleted 70–90% of gd T cells at (ref. 24) are also required for gd17 cell development. early time points, but the population gradually recovered In mice, the TCRg locus consists of seven Vg (Vg1–Vg7) genes (Supplementary Fig. 2c), probably due to the development of that are closely correlated with effector functions, although in antibodies against this mAb. Nonetheless, the anti-gd TCR mAb most strains Vg3 is a pseudogene25. IL-17 is produced by Vg4 þ treatment greatly decreased the gd17 population (Fig. 2e; and Vg6 þ gd T cells26 (Heilig and Tonegawa’s nomenclature27). Supplementary Fig. 2d), suggesting that anti-gd TCR mAb effectively depleted gd17 cells, at least at earlier times. IL-17 Although overall gene expression patterns are similar between À these two subsets18, each subset has distinct features. Vg6 þ gd T production in the gd TCR population was not elevated in these mice (Supplementary Fig. 2d). Most populations of CD4 þ cells express the invariant Vg6/Vd1 TCR, develop only in the late- À / À embryonic thymus and preferentially localize in the uterus, vagina, T cells, including Th17 cells, remained depleted in Il1rn lung, dermis and peritoneal cavity28,29. On the other hand, Vg4 þ mice on day 11 after anti-CD4 mAb treatment (Fig. 2f; gd T cells have a more diverse TCR repertoire, and develop in Supplementary Fig. 2e). These results suggest that both gd T cells and CD4 þ T cells are involved in the development of arthritis both foetal and adult thymus. Subsequently, they circulate in À / À 30 in Il1rn mice. However, arthritis developed normally in blood and reside in the dermis and secondary lymphoid organs . À / À À / À þ Tcrd Il1rn mice (Supplementary Fig. 2f), and IL-17- However, the differences between the pathogenic roles of Vg6 À À À and Vg4 þ gd17 cells, particularly the contribution of Vg6 þ gd17 producing CD4 CD8 gdTCR T cells were increased in the cells to inflammatory diseases, remain unclear. LNs and joints of these mice (Supplementary Fig. 2g). The mechanism of gd17 cell migration into inflammatory sites is also poorly understood. Recent gene array analysis showed that Both cd17 and CD4 þ T cells collaborate to develop arthritis. the expression of chemokine receptors such as CCR6, CCR2 and Next, we directly examined the pathogenic role of gd T cells and CXCR6 is upregulated in gd17 thymocytes18. Moreover, CCR6 CD4 þ T cells by adoptive cell transfer. gd T cells derived from expression is often used as a marker of gd17 cells17. However, it Cd4 À / À Il1rn À / À mice and/or CD4 þ T cells derived from remains unknown whether these chemokine receptors function in Tcrd À / À Il1rn À / À mice were transferred into scid/scid mice. gd17 cell migration. We found that scid/scid mice that received transfer of whole- IL-1 receptor antagonist (IL-1Ra, gene symbol: Il1rn)isan Il1rn À / À T cells or a mixture of gd and CD4 þ T cells developed endogenous inhibitor of IL-1 activity that competes with IL-1a arthritis, whereas those that received transfer of gd or CD4 þ and IL-1b for IL-1R binding.
Load more

Recommended publications
  • Toxicogenomics Article
    Toxicogenomics Article Discovery of Novel Biomarkers by Microarray Analysis of Peripheral Blood Mononuclear Cell Gene Expression in Benzene-Exposed Workers Matthew S. Forrest,1 Qing Lan,2 Alan E. Hubbard,1 Luoping Zhang,1 Roel Vermeulen,2 Xin Zhao,1 Guilan Li,3 Yen-Ying Wu,1 Min Shen,2 Songnian Yin,3 Stephen J. Chanock,2 Nathaniel Rothman,2 and Martyn T. Smith1 1School of Public Health, University of California, Berkeley, California, USA; 2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA; 3National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China were then ranked and selected for further exam- Benzene is an industrial chemical and component of gasoline that is an established cause of ination using several forms of statistical analysis. leukemia. To better understand the risk benzene poses, we examined the effect of benzene expo- We also specifically examined the expression sure on peripheral blood mononuclear cell (PBMC) gene expression in a population of shoe- of all cytokine genes on the array under the factory workers with well-characterized occupational exposures using microarrays and real-time a priori hypothesis that these key genes polymerase chain reaction (PCR). PBMC RNA was stabilized in the field and analyzed using a involved in immune function are likely to be comprehensive human array, the U133A/B Affymetrix GeneChip set. A matched analysis of six altered by benzene exposure (Aoyama 1986). exposed–control pairs was performed. A combination of robust multiarray analysis and ordering We then attempted to confirm the array find- of genes using paired t-statistics, along with bootstrapping to control for a 5% familywise error ings for the leading differentially expressed rate, was used to identify differentially expressed genes in a global analysis.
    [Show full text]
  • OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- Α Release from Human CCR2 + Inflammatory Monocytes
    OSCAR Is a Receptor for Surfactant Protein D That Activates TNF- α Release from Human CCR2 + Inflammatory Monocytes This information is current as Alexander D. Barrow, Yaseelan Palarasah, Mattia Bugatti, of September 25, 2021. Alex S. Holehouse, Derek E. Byers, Michael J. Holtzman, William Vermi, Karsten Skjødt, Erika Crouch and Marco Colonna J Immunol 2015; 194:3317-3326; Prepublished online 25 February 2015; Downloaded from doi: 10.4049/jimmunol.1402289 http://www.jimmunol.org/content/194/7/3317 Supplementary http://www.jimmunol.org/content/suppl/2015/02/24/jimmunol.140228 http://www.jimmunol.org/ Material 9.DCSupplemental References This article cites 40 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/194/7/3317.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology OSCAR Is a Receptor for Surfactant Protein D That Activates TNF-a Release from Human CCR2+ Inflammatory Monocytes Alexander D.
    [Show full text]
  • CXCL16 Suppresses Liver Metastasis of Colorectal Cancer by Promoting
    Kee et al. BMC Cancer 2014, 14:949 http://www.biomedcentral.com/1471-2407/14/949 RESEARCH ARTICLE Open Access CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages Ji-Ye Kee1†, Aya Ito1,2†, Shozo Hojo3, Isaya Hashimoto3, Yoshiko Igarashi2, Koichi Tsuneyama4, Kazuhiro Tsukada3, Tatsuro Irimura5, Naotoshi Shibahara2, Ichiro Takasaki9, Akiko Inujima2, Takashi Nakayama6, Osamu Yoshie7, Hiroaki Sakurai8, Ikuo Saiki1 and Keiichi Koizumi2*† Abstract Background: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. Methods: We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis- related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. Results: CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3- mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α.
    [Show full text]
  • CXC Chemokine Ligand 16 Regulates the Cell Surface Expression of 10
    A Disintegrin and Metalloproteinase 10-Mediated Cleavage and Shedding Regulates the Cell Surface Expression of CXC Chemokine Ligand 16 This information is current as of October 2, 2021. Peter J. Gough, Kyle J. Garton, Paul T. Wille, Marcin Rychlewski, Peter J. Dempsey and Elaine W. Raines J Immunol 2004; 172:3678-3685; ; doi: 10.4049/jimmunol.172.6.3678 http://www.jimmunol.org/content/172/6/3678 Downloaded from References This article cites 35 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/172/6/3678.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Disintegrin and Metalloproteinase 10-Mediated Cleavage and Shedding Regulates the Cell Surface Expression of CXC Chemokine Ligand 16 Peter J. Gough,2* Kyle J. Garton,* Paul T.
    [Show full text]
  • HIV-1 Tat Protein Mimicry of Chemokines
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13153–13158, October 1998 Immunology HIV-1 Tat protein mimicry of chemokines ADRIANA ALBINI*, SILVANO FERRINI*, ROBERTO BENELLI*, SABRINA SFORZINI*, DANIELA GIUNCIUGLIO*, MARIA GRAZIA ALUIGI*, AMANDA E. I. PROUDFOOT†,SAMI ALOUANI†,TIMOTHY N. C. WELLS†, GIULIANO MARIANI‡,RONALD L. RABIN§,JOSHUA M. FARBER§, AND DOUGLAS M. NOONAN*¶ *Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; †Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, 14 chemin des Aulx, 1228 Plan-les Ouates, Geneva, Switzerland; ‡Dipartimento di Medicina Interna, Medicina Nucleare, University of Genova, Viale Benedetto XV, 6, 16132 Genoa, Italy; and §National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N228 MSC 1888, Bethesda, MD 20892 Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved August 25, 1998 (received for review June 24, 1998) ABSTRACT The HIV-1 Tat protein is a potent chemoat- ceptors for some dual tropic HIV-1 strains (10, 11). A CCR2 tractant for monocytes. We observed that Tat shows conserved polymorphism has been found to correlate with delayed amino acids corresponding to critical sequences of the che- progression to AIDS (12, 13). mokines, a family of molecules known for their potent ability We report here that the HIV-1 Tat protein and the peptide to attract monocytes. Synthetic Tat and a peptide (CysL24–51) encompassing the cysteine-rich and core regions induce per- encompassing the ‘‘chemokine-like’’ region of Tat induced a tussis toxin sensitive Ca21 fluxes in monocytes.
    [Show full text]
  • CCR2 Enhances CD25 Expression by Foxp3+ Regulatory T Cells and Regulates Their Abundance Independently of Chemotaxis and CCR2+ Myeloid Cells
    Cellular & Molecular Immunology www.nature.com/cmi ARTICLE CCR2 enhances CD25 expression by FoxP3+ regulatory T cells and regulates their abundance independently of chemotaxis and CCR2+ myeloid cells Yifan Zhan 1,2,3, Nancy Wang 4, Ajithkumar Vasanthakumar1,2,4, Yuxia Zhang3, Michael Chopin1,2, Stephen L. Nutt 1,2, Axel Kallies1,2,4 and Andrew M. Lew1,2,4 A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3+ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT) and CCR2−/− strains. Thus, CCR2 deficiency resulted in profound loss of CD25hi FoxP3+ Tregs in secondary lymphoid organs as well as in peripheral tissues. CCR2−/− Treg cells were also functionally inferior to WT cells. Interestingly, these changes to Treg cells did not depend on CCR2+ monocytes/moDCs (the cells where CCR2 receptors are most abundant). Rather, we demonstrated that CCR2 was required for TLR- stimulated, but not TCR- or IL-2-stimulated, CD25 upregulation on Treg cells. Thus, we propose that CCR2 signaling can increase the fitness of FoxP3+ Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells. Cellular & Molecular Immunology (2020) 17:123–132; https://doi.org/10.1038/s41423-018-0187-8 INTRODUCTION production by T cells. Beyond chemotaxis, no other role has been CCR2 is a chemokine receptor known for its role in monocyte ascribed to CCR2 in Tregs.
    [Show full text]
  • Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3+ Regulatory T Cells
    Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3+ Regulatory T Cells This information is current as Hyung W. Lim, Jeeho Lee, Peter Hillsamer and Chang H. of September 28, 2021. Kim J Immunol 2008; 180:122-129; ; doi: 10.4049/jimmunol.180.1.122 http://www.jimmunol.org/content/180/1/122 Downloaded from References This article cites 44 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/180/1/122.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Th17 Cells Share Major Trafficking Receptors with Both Polarized Effector T Cells and FOXP3؉ Regulatory T Cells1 Hyung W. Lim,* Jeeho Lee,* Peter Hillsamer,† and Chang H. Kim2* It is a question of interest whether Th17 cells express trafficking receptors unique to this Th cell lineage and migrate specifically to certain tissue sites.
    [Show full text]
  • Dendritic Cells Maintain Anti-Tumor Immunity by Positioning CD8 Skin-Resident Memory T Cells
    Published Online: 6 August, 2021 | Supp Info: http://doi.org/10.26508/lsa.202101056 Downloaded from life-science-alliance.org on 26 September, 2021 Research Article Dendritic cells maintain anti-tumor immunity by positioning CD8 skin-resident memory T cells Jennifer L Vella1, Aleksey Molodtsov1, Christina V Angeles2 , Bruce R Branchini3, Mary Jo Turk1,4, Yina H Huang1,4,5 Tissue-resident memory (TRM) T cells are emerging as critical maintenance, leading us to determine whether specific accessory components of the immune response to cancer; yet, requirements cells maintain TRM cell homeostasis within a tissue niche. for their ongoing function and maintenance remain unclear. APCs The immune response to solid cancers is limited by availability promote TRM cell differentiation and re-activation but have not of neoantigens, tolerance to self-antigens, T-cell dysfunction, and been implicated in sustaining TRM cell responses. Here, we immunosuppression within the tumor microenvironment. Check- identified a novel role for dendritic cells in supporting TRM to point blockade immunotherapy, which blocks inhibitory receptors melanoma. We showed that CD8 TRM cells remain in close prox- such as PD-1 and CTLA-4, can reverse T-cell dysfunction and when imity to dendritic cells in the skin. Depletion of CD11c+ cells results combined achieves >50% patient responsiveness. However, pre- in rapid disaggregation and eventual loss of melanoma-specific dicting patient responders remains a challenge. Recently, expression TRM cells. In addition, we determined that TRM migration and/or of TRM cell markers in tumor infiltrating lymphocytes has been re- persistence requires chemotaxis and adhesion mediated by the ported to correlate with patient responsiveness and prolonged CXCR6/CXCL16 axis.
    [Show full text]
  • Cytokine Modulators As Novel Therapies for Airway Disease
    Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 18: Suppl. 34, 67s–77s European Respiratory Journal DOI: 10.1183/09031936.01.00229901 ISSN 0904-1850 Printed in UK – all rights reserved ISBN 1-904097-20-0 Cytokine modulators as novel therapies for airway disease P.J. Barnes Cytokine modulators as novel therapies for airway disease. P.J. Barnes. #ERS Correspondence: P.J. Barnes Journals Ltd 2001. Dept of Thoracic Medicine ABSTRACT: Cytokines play a critical role in orchestrating and perpetuating National Heart & Lung Institute inflammation in asthma and chronic obstructive pulmonary disease (COPD), and Imperial College Dovehouse Street several specific cytokine and chemokine inhibitors are now in development for the future London SW3 6LY therapy of these diseases. UK Anti-interleukin (IL)-5 is very effective at reducing peripheral blood and airway Fax: 0207 3515675 eosinophil numbers, but does not appear to be effective against symptomatic asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in Keywords: Chemokine receptor asthma. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, cytokine as systemic delivery causes side-effects. Inhibition of tumour necrosis factor-a may be interleukin-4 useful in severe asthma and for treating severe COPD with systemic features. interleukin-5 interleukin-9 Many chemokines are involved in the inflammatory response of asthma and COPD interleukin-10 and several low-molecular-weight inhibitors of chemokine receptors are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which Received: March 26 2001 block neutrophil and monocyte chemotaxis) are in clinical development for the Accepted April 25 2001 treatment of asthma and COPD respectively.
    [Show full text]
  • Role of Chemokines in Hepatocellular Carcinoma (Review)
    ONCOLOGY REPORTS 45: 809-823, 2021 Role of chemokines in hepatocellular carcinoma (Review) DONGDONG XUE1*, YA ZHENG2*, JUNYE WEN1, JINGZHAO HAN1, HONGFANG TUO1, YIFAN LIU1 and YANHUI PENG1 1Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051; 2Medical Center Laboratory, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, P.R. China Received September 5, 2020; Accepted December 4, 2020 DOI: 10.3892/or.2020.7906 Abstract. Hepatocellular carcinoma (HCC) is a prevalent 1. Introduction malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges Hepatocellular carcinoma (HCC) is the sixth most common for the treatment of HCC is the prevention or management type of cancer worldwide and the third leading cause of of recurrence and metastasis of HCC. It has been found that cancer-associated death (1). Most patients cannot undergo chemokines and their receptors serve a pivotal role in HCC radical surgery due to the presence of intrahepatic or distant progression. In the present review, the literature on the multi- organ metastases, and at present, the primary treatment methods factorial roles of exosomes in HCC from PubMed, Cochrane for HCC include surgery, local ablation therapy and radiation library and Embase were obtained, with a specific focus on intervention (2). These methods allow for effective treatment the functions and mechanisms of chemokines in HCC. To and management of patients with HCC during the early stages, date, >50 chemokines have been found, which can be divided with 5-year survival rates as high as 70% (3). Despite the into four families: CXC, CX3C, CC and XC, according to the continuous development of traditional treatment methods, the different positions of the conserved N-terminal cysteine resi- issue of recurrence and metastasis of HCC, causing adverse dues.
    [Show full text]
  • CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza a Virus
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.24.436901; this version posted March 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus 2 Woojong Lee1, Brock Kingstad-Bakke1, Ross M. Kedl2, Yoshihiro Kawaoka1, and, M. 3 Suresh1,3* 4 Affiliations: 5 1Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, 6 53706, WI, USA 7 2Department of Immunology and Microbiology, School of Medicine, University of 8 Colorado, Aurora, CO, USA 9 3 Lead Author 10 11 * To whom correspondence should be addressed: [email protected] 12 13 Word Count for the abstract = 248 14 15 16 17 18 19 20 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.24.436901; this version posted March 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 21 Abstract 22 Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T-cell based 23 vaccines against respiratory viral pathogens such as influenza A virus (IAV). Chemokine 24 receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the 25 establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination 26 adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) 27 IAV nucleoprotein-specific lung TRMs, to determine whether CCR2 and monocyte 28 infiltration are essential for vaccine-induced TRM development and protective immunity to 29 IAV in lungs.
    [Show full text]
  • A Novel Role for Constitutively Expressed Epithelial-Derived Chemokines As Antibacterial Peptides in the Intestinal Mucosa
    ARTICLES nature publishing group A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa K K o t a r s k y 1 , K M S i t n i k 1 , H S t e n s t a d 1 , H K o t a r s k y 2 , A S c h m i d t c h e n 3 , M K o s l o w s k i 4 , J We h k a m p 4 a n d W W A g a c e 1 Intestinal-derived chemokines have a central role in orchestrating immune cell influx into the normal and inflamed intestine. Here, we identify the chemokine CCL6 as one of the most abundant chemokines constitutively expressed by both murine small intestinal and colonic epithelial cells. CCL6 protein localized to crypt epithelial cells, was detected in the gut lumen and reached high concentrations at the mucosal surface. Its expression was further enhanced in the small intestine following in vivo administration of LPS or after stimulation of the small intestinal epithelial cell line, mICc12 , with IFN , IL-4 or TNF . Recombinant- and intestinal-derived CCL6 bound to a subset of the intestinal microflora and displayed antibacterial activity. Finally, the human homologs to CCL6, CCL14 and CCL15 were also constitutively expressed at high levels in human intestinal epithelium, were further enhanced in inflammatory bowel disease and displayed similar antibacterial activity. These findings identify a novel role for constitutively expressed, epithelial-derived chemokines as antimicrobial peptides in the intestinal mucosa.
    [Show full text]