Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes

Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes Ruobing Li , Nicolas Perez , Subha Karumuthil-Melethil and Chenthamarakshan Vasu Department of Surgery, University of Illinois at Chicago, Chicago, Illinois Address correspondence and reprint requests to Chenthamar...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2007-09, Vol.56 (9), p.2251-2259
Hauptverfasser: RUOBING LI, PEREZ, Nicolas, KARUMUTHIL-MELETHIL, Subha, VASU, Chenthamarakshan
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container_issue 9
container_start_page 2251
container_title Diabetes (New York, N.Y.)
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creator RUOBING LI
PEREZ, Nicolas
KARUMUTHIL-MELETHIL, Subha
VASU, Chenthamarakshan
description Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes Ruobing Li , Nicolas Perez , Subha Karumuthil-Melethil and Chenthamarakshan Vasu Department of Surgery, University of Illinois at Chicago, Chicago, Illinois Address correspondence and reprint requests to Chenthamarakshan Vasu, Department of Surgery, University of Illinois at Chicago, 909 S. Wolcott, COMRB 7113, M/C790, Chicago, IL 60612. E-mail: chenta{at}uic.edu Abstract OBJECTIVE— The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice. RESEARCH DESIGN AND METHODS— Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD- Scid and wild-type mice. RESULTS— The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD- Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes. CONCLUSIONS— Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease. APC, antigen-presenting cell CFSE, carboxyfluorescein succinimidyl ester FACS, fluorescence-activated cell sorting IFN-γ, γ interferon IL, interleukin MHC, major histocompatibility complex SLO, secondary lymphoid organ TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 June 2007. DOI: 10.2337/db07-0502. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0
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Wolcott, COMRB 7113, M/C790, Chicago, IL 60612. E-mail: chenta{at}uic.edu Abstract OBJECTIVE— The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice. RESEARCH DESIGN AND METHODS— Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD- Scid and wild-type mice. RESULTS— The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD- Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes. CONCLUSIONS— Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease. APC, antigen-presenting cell CFSE, carboxyfluorescein succinimidyl ester FACS, fluorescence-activated cell sorting IFN-γ, γ interferon IL, interleukin MHC, major histocompatibility complex SLO, secondary lymphoid organ TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 June 2007. DOI: 10.2337/db07-0502. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0502 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 17, 2007. Received April 16, 2007. DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db07-0502</identifier><identifier>PMID: 17596402</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adoptive Transfer ; Animals ; Antibodies ; Antigens ; Biological and medical sciences ; Bone marrow ; Bone Marrow - immunology ; Care and treatment ; Cytokines ; Cytokines - analysis ; Diabetes ; Diabetes Mellitus, Type 1 - immunology ; Diabetes Mellitus, Type 1 - pathology ; Diabetes. Impaired glucose tolerance ; Diagnosis ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Female ; Flow Cytometry ; Glucose ; Health aspects ; Hyperglycemia ; Hyperglycemia - immunology ; Laboratories ; Lymphatic system ; Lymphocyte Activation ; Medical sciences ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Pancreas - pathology ; Peptides ; Research design ; Spleen ; Spleen - immunology ; T-Lymphocytes - immunology ; Type 1 diabetes</subject><ispartof>Diabetes (New York, N.Y.), 2007-09, Vol.56 (9), p.2251-2259</ispartof><rights>2007 INIST-CNRS</rights><rights>COPYRIGHT 2007 American Diabetes Association</rights><rights>Copyright American Diabetes Association Sep 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c619t-7917c8c0135666040ef5c1679ef7c4fb89d952c79fffbedb810c9f54d064253</citedby><cites>FETCH-LOGICAL-c619t-7917c8c0135666040ef5c1679ef7c4fb89d952c79fffbedb810c9f54d064253</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=19054823$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17596402$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RUOBING LI</creatorcontrib><creatorcontrib>PEREZ, Nicolas</creatorcontrib><creatorcontrib>KARUMUTHIL-MELETHIL, Subha</creatorcontrib><creatorcontrib>VASU, Chenthamarakshan</creatorcontrib><title>Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes Ruobing Li , Nicolas Perez , Subha Karumuthil-Melethil and Chenthamarakshan Vasu Department of Surgery, University of Illinois at Chicago, Chicago, Illinois Address correspondence and reprint requests to Chenthamarakshan Vasu, Department of Surgery, University of Illinois at Chicago, 909 S. Wolcott, COMRB 7113, M/C790, Chicago, IL 60612. E-mail: chenta{at}uic.edu Abstract OBJECTIVE— The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice. RESEARCH DESIGN AND METHODS— Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD- Scid and wild-type mice. RESULTS— The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD- Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes. CONCLUSIONS— Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease. APC, antigen-presenting cell CFSE, carboxyfluorescein succinimidyl ester FACS, fluorescence-activated cell sorting IFN-γ, γ interferon IL, interleukin MHC, major histocompatibility complex SLO, secondary lymphoid organ TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 June 2007. DOI: 10.2337/db07-0502. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0502 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 17, 2007. Received April 16, 2007. DIABETES</description><subject>Adoptive Transfer</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Biological and medical sciences</subject><subject>Bone marrow</subject><subject>Bone Marrow - immunology</subject><subject>Care and treatment</subject><subject>Cytokines</subject><subject>Cytokines - analysis</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diagnosis</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Glucose</subject><subject>Health aspects</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - immunology</subject><subject>Laboratories</subject><subject>Lymphatic system</subject><subject>Lymphocyte Activation</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Pancreas - pathology</subject><subject>Peptides</subject><subject>Research design</subject><subject>Spleen</subject><subject>Spleen - immunology</subject><subject>T-Lymphocytes - immunology</subject><subject>Type 1 diabetes</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0u9r1DAYB_AiijtPX_gPSFAURDqTtEmal-ep2-Bkwk7wXUjTJ11Gr7klrXP_vTmucEwOJS8SwidPfn2z7CXBp7QoxMemxiLHDNNH2YzIQuYFFT8fZzOMCc2JkOIkexbjDcaYp_Y0OyGCSV5iOst-fPI9oG86BH-HLiLS6HsACwH6wekOnfuN61t05QZA1ge0GAcfQJvB_QK0zpfQdRG5Hq3vt4AI-ux0DQPE59kTq7sIL6Z-nl19_bJenuery7OL5WKVG07kkAtJhKkMJgXjnOMSg2WGcCHBClPaupKNZNQIaa2toakrgo20rGwwLykr5tm7fdVt8LcjxEFtXDTpSLoHP0bFK0qKsiT_hRSXEhcEJ_j6L3jjx9CnKyhKeFlhznfbvtmjVnegXG_9ELTZVVQLwiteYMZEUvkR1UIPQXfpza1L0w_86RGfWgMbZ44ueP9gQTID_B5aPcaoqrPVvw4zWeO7DlpQ6U-Wl0drm-BjTIFQ2-A2OtwrgtUucmoXObWLXLKvpjcb6w00BzllLIG3E9DR6M4G3RsXD05iVlap6Dz7sHfXrr2-cwFUM8XpMGBcSUUpI8Ufe5Pl4Q</recordid><startdate>20070901</startdate><enddate>20070901</enddate><creator>RUOBING LI</creator><creator>PEREZ, Nicolas</creator><creator>KARUMUTHIL-MELETHIL, Subha</creator><creator>VASU, Chenthamarakshan</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20070901</creationdate><title>Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes</title><author>RUOBING LI ; PEREZ, Nicolas ; KARUMUTHIL-MELETHIL, Subha ; VASU, Chenthamarakshan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c619t-7917c8c0135666040ef5c1679ef7c4fb89d952c79fffbedb810c9f54d064253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adoptive Transfer</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antigens</topic><topic>Biological and medical sciences</topic><topic>Bone marrow</topic><topic>Bone Marrow - immunology</topic><topic>Care and treatment</topic><topic>Cytokines</topic><topic>Cytokines - analysis</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diabetes Mellitus, Type 1 - pathology</topic><topic>Diabetes. 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Wolcott, COMRB 7113, M/C790, Chicago, IL 60612. E-mail: chenta{at}uic.edu Abstract OBJECTIVE— The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice. RESEARCH DESIGN AND METHODS— Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD- Scid and wild-type mice. RESULTS— The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD- Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes. CONCLUSIONS— Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease. APC, antigen-presenting cell CFSE, carboxyfluorescein succinimidyl ester FACS, fluorescence-activated cell sorting IFN-γ, γ interferon IL, interleukin MHC, major histocompatibility complex SLO, secondary lymphoid organ TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 June 2007. DOI: 10.2337/db07-0502. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0502 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 17, 2007. Received April 16, 2007. DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>17596402</pmid><doi>10.2337/db07-0502</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects Adoptive Transfer
Animals
Antibodies
Antigens
Biological and medical sciences
Bone marrow
Bone Marrow - immunology
Care and treatment
Cytokines
Cytokines - analysis
Diabetes
Diabetes Mellitus, Type 1 - immunology
Diabetes Mellitus, Type 1 - pathology
Diabetes. Impaired glucose tolerance
Diagnosis
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Female
Flow Cytometry
Glucose
Health aspects
Hyperglycemia
Hyperglycemia - immunology
Laboratories
Lymphatic system
Lymphocyte Activation
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Pancreas - pathology
Peptides
Research design
Spleen
Spleen - immunology
T-Lymphocytes - immunology
Type 1 diabetes
title Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes
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