George C Tsokos

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

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Publications (466)2172.25 Total impact

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    ABSTRACT: Abstract Objective: Foxp3(+) regulatory T cells (Treg) are pivotal for the maintenance of peripheral tolerance and prevent development of autoimmune diseases. We have reported that calcium/calmodulin-dependent protein kinase IV (CaMK4) deficient MRL/lpr mice display less disease activity by promoting IL-2 production and increasing the activity of Treg cells. To further define the mechanism of CaMK4 on Treg cells in systemic lupus erythematosus (SLE), we used the Foxp3-GFP reporter mice and treated them with KN-93, an inhibitor of CaMK4. Methods: We generated MRL/lpr Foxp3-GFP mice to record Treg cells; stimulated naïve CD4(+) T cells from MRL/lpr Foxp3-GFP mice under Treg polarizing conditions in the absence or presence of KN-93; evaluated the number of GFP positive cells in lymphoid organs and examined skin and kidney pathology at 16 weeks of age. We also examined the infiltration of cells and recruitment of Treg cells in the kidney. Results: We show that culture of MRL/lpr Foxp3-GFP T cells in the presence of KN-93 promotes Treg differentiation in a dose-dependent manner. Treatment of MRL/lpr Foxp3-GFP mice with KN-93 results in a significant induction of Treg cells in the spleen, peripheral lymph nodes and peripheral blood and this is accompanied by decreased skin and kidney damage. Notably, KN-93 clearly diminishes the accumulation of inflammatory cells along with reciprocally increased Treg cells in target organ. Conclusion: Our results indicate that KN-93 treatment enhances the generation of Treg cells in vitro and in vivo highlighting its potential therapeutic use for the treatment of human autoimmune diseases.
    Autoimmunity 05/2014; · 2.77 Impact Factor
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    ABSTRACT: Abstract Epigenetic events play a central role in the priming, differentiation and subset determination of T lymphocytes. Through their influence on chromatin conformation and DNA-accessibility to transcription factors and RNA polymerases, epigenetic marks allow or prevent gene expression and control cellular functions including cytokine expression. CpG-DNA methylation and post-translational modifications to histone tails are the two most well accepted epigenetic mechanisms. The involvement of epigenetic mechanisms in the pathogenesis of systemic lupus erythematosus (SLE) has been suggested by the development of lupus-like symptoms by individuals who received procainamide or hydralazine treatment resulting in a reduction of CpG-DNA methylation. To date, a growing body of literature indicates that the deregulation of cytokine expression through epigenetic disturbances can result in altered immune responses and autoimmune reactions. Over the past decade, various global and regional epigenetic alterations have been reported in immune cells from patients with SLE and other autoimmune disorders. More recently, the molecular mechanisms that result in epigenetic disturbances have been addressed, and deregulated transcription factor networks have been demonstrated to mediate epigenetic alterations in B and T lymphocytes from SLE patients. A better understanding of the molecular events that contribute to epigenetic alterations and subsequent immune imbalance is essential for the establishment of disease biomarkers and identification of potential therapeutic targets.
    Autoimmunity 04/2014; · 2.77 Impact Factor
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    ABSTRACT: Protein phosphatase 2A (PP2A) is a highly conserved and ubiquitous serine/threonine phosphatase. We have previously shown that PP2A expression is increased in T cells of SLE patients and this increased expression and activity of PP2A plays a central role in the molecular pathogenesis of SLE. Although the control of PP2A expression has been the focus of many studies, many aspects of its regulation still remain poorly understood. In this study, we describe a novel mechanism of PP2A regulation. We propose that the transcription factor Ikaros binds to a variant site in the first intron of PP2A and modulates its expression. Exogenous expression of Ikaros leads to reduced levels of PP2Ac message as well as protein. Conversely, siRNA enabled silencing of Ikaros enhances the expression of PP2A, suggesting that Ikaros acts as a suppressor of PP2A expression. ChIP analysis further proved that Ikaros is recruited to this site in T cells. We also attempt to delineate the mechanism of Ikaros mediated PP2Ac gene suppression. We show that Ikaros mediated suppression of PP2A expression is at least partially dependent on the recruitment of the histone deacetylase HDAC1 to this intronic site. We conclude that the transcription factor Ikaros can regulate the expression of PP2A by binding to a site in the first intron and modulating chromatin modifications at this site via recruitment of HDAC1.
    Journal of Biological Chemistry 04/2014; · 4.65 Impact Factor
  • Katalin Kis-Toth, George C Tsokos
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    ABSTRACT: Signaling lymphocyte activation molecule family (SLAMF)2/CD48 is a coactivator and adhesion molecule on cells with hematopoietic origin. It ligates mainly SLAMF4 on effector/memory CD8(+) T cells and NK cells, suggesting a potential role during viral infection, with SLAMF2 acting as a ligand to activate SLAMF4-bearing cells. The ability of SLAMF2 to signal on its own after it is engaged and the functional consequences are largely unknown. We found that cytosolic DNA-activated dendritic cells (DCs) upregulate the expression of SLAMF2 molecules. Using anti-SLAMF2 Ab and SLAMF4 recombinant protein, we found that SLAMF2 engagement activates immature DCs and, more interestingly, prolongs the survival of DNA-activated DCs by inhibiting IFN-β production and IFN-β-induced apoptosis and promotes the production of the granzyme B inhibitor protease inhibitor-9. Thus, SLAMF2 can serve as a survival molecule for DNA-activated DCs during their interaction with SLAMF4-expressing cytotoxic T cells. Based on our results, we propose that SLAMF2 engagement regulates adaptive immune responses by providing longer access of putative APCs to virus-specific effector T cells by prolonging the time frame of effective stimulation.
    The Journal of Immunology 03/2014; · 5.52 Impact Factor
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    ABSTRACT: Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.
    The Journal of clinical investigation 03/2014; · 15.39 Impact Factor
  • Trevor E. Davis, Katalin Kis‐Toth, George C. Tsokos
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    ABSTRACT: Background/Purpose:MicroRNA (miRNA, miR) are short RNA species (20–23 nt) that act post-transcriptionally modulating messenger RNA (mRNA) translation or stability. They control many biological processes including cell differentiation and homeostasis. Abnormal levels of miRNA have been implicated in cancers and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Steroids are first line anti-inflammatory medications that act through transcriptional or posttranscriptional gene regulation. In multiple instances steroids cause mRNA destabilization indicating a potential role for miRNA.Previously, using high-throughput microarray analysis, we found that methylprednisolone (MP) decreased miR-155 expression in CD4+ T cells in vitro. miR-155 is highly expressed in immune cells and influential in cell differentiation. This influence may in part be mediated through suppression of cytokine signaling 1 (SOCS1), a known target of miR-155. SOCS1 inhibits multiple JAK/STAT pathways, which may inhibit cell proliferation and differentiation. Steroids have also been shown to inhibit proliferation, differentiation and the JAK/STAT pathways. Steroids through blocking the IL-12/STAT4 pathway inhibit Th1 differentiation. This pathway is in part controlled by SOCS1, which should be under the control of miR-155. Following our previous work here we explore the potential mechanism of action of miR-155 during MP treatment of T cells.Methods:Total or naive CD4+ T cells were isolated from peripheral blood of healthy donors and activated by anti-CD3/anti-CD28 antibodies for up to 5 days with or without Th1 polarizing conditions (10 nM IL-12 and 5 mM anti-IL-4 neutralizing antibody) and with or without exposure to 10−6 M of methylprednisolone. Some cells were first transfected with mimic miR-155, control mimic miR, anti-miR-155, or control anti-miR by electroporation. Effects on miR-155, SOCS1, STAT phosphorylation, IFNg production and Th1 differentiation were monitored using flow cytometry, RNA quantification by PCR, and protein quantification by ELISA or western blot analysis.Results:Activated T cells treated with MP decrease miR-155 expression and increase SOCS1 expression. In turn, SOCS1 decreases JAK/STAT signaling and inhibits response to cytokines, notably IL-12, resulting in decreased IFNg production by activated T cells.Conclusion:We found that the anti-inflammatory effects of MP, at least in part, act through decreasing miR-155 in T cells by inhibiting JAK/STAT signaling and cytokine production through modulating SOCS1 expression. Based on our findings we propose that miR-155 inhibition could be utilized to suppress inflammation without the myriad of side effects currently inherent in chronic steroid therapy.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Complement system is activated in patients with trauma. Although complement activation is presumed to contribute to organ damage and constitutional symptoms, little is known about the involved mechanisms. Because complement components may deposit on RBCs, we asked whether complement deposits on the surface of RBC in trauma and whether such deposition alters RBC function. A prospective experimental study. Research laboratory. Blood samples collected from 42 trauma patients and 21 healthy donors. None. RBC and sera were collected from trauma patients and control donors. RBCs from trauma patients (n = 40) were found to display significantly higher amounts of C4d on their surface by flow cytometry compared with RBCs from control (n = 17) (p < 0.01). Increased amounts of iC3b were found in trauma sera (n = 27) (vs 12 controls, p < 0.01) by enzyme-linked immunosorbent assay. Incubation of RBC from universal donors (type O, Rh negative) with trauma sera (n = 10) promoted C4d deposition on their surface (vs six controls, p< 0.05). Complement-decorated RBC (n = 6) displayed limited their deformability (vs six controls, p < 0.05) in two-dimensional microchannel arrays. Incubation of RBC with trauma sera (n = 10) promoted the phosphorylation of band 3, a cytoskeletal protein important for the function of the RBC membrane (vs eight controls, p < 0.05), and also accelerated calcium influx (n = 9) and enhanced nitric oxide production (n = 12) (vs four and eight controls respectively, p < 0.05) in flow cytometry. Our study found the presence of extensive complement activation in trauma patients and presents new evidence in support of the hypothesis that complement activation products deposit on the surface of RBC. Such deposition could limit RBC deformability and promote the production of nitric oxide. Our findings suggest that RBC in trauma patients malfunction, which may explain organ damage and constitutional symptoms that is not accounted for otherwise by previously known pathophysiologic mechanisms.
    Critical care medicine 01/2014; · 6.37 Impact Factor
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    Alexandros P Grammatikos, George C Tsokos
    01/2014;
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    ABSTRACT: T cells from patients with SLE exhibit reduced expression of the critical T cell receptor (TCR) associated CD3 zeta signaling chain, and are poor producers of the vital cytokine IL-2. By oligonucleotide pulldown and mass spectrometry discovery approaches, we identified the splicing regulator serine arginine-rich splicing factor (SRSF) 1 or splicing factor 2 / alternative splicing factor (SF2/ASF) to be important in the expression of CD3 zeta chain. Importantly, increases in the expression of SRSF1 rescued IL-2 production in T cells from patients with SLE. In this study, we investigated the regulation of SRSF1 expression in resting and activated human T cells. We found that T cell stimulation induced a rapid and significant increase in mRNA expression of SRSF1, however protein expression levels did not correlate with this increase. Co-engagement of CD28 induced a similar mRNA induction and reduction in protein levels. Proteasomal but not lysosomal degradation was involved in this downregulation as evidenced by blocking with specific inhibitors MG132 and Bafilomycin respectively. Immunoprecipitation studies showed increased ubiquitination of SRSF1 in activated T cells. Interestingly, T cells from patients with SLE showed increased ubiquitination of SRSF1 when compared to those from healthy individuals. Our results demonstrate a novel mechanism of regulation of the splicing factor SRSF1 in human T cells and a potential molecular mechanism that controls its expression in SLE.
    Journal of Biological Chemistry 12/2013; · 4.65 Impact Factor
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    ABSTRACT: Systemic Lupus Erythematosus (SLE) remains a challenging disease to diagnose and follow, as no reliable biomarkers are known to date. We designed a gene expression panel with 40 genes known to play a role in SLE pathogenesis. We found that the combined expression of these genes in SLE T cells can accurately differentiate SLE from healthy individuals and patients with other autoimmune diseases. The accuracy of the test increased further (83%) when only three out of the initial genes (OAS2, CD70 and IL10) were used. A T cell score, calculated from the combined expression levels of these genes, correlated positively with various SLE activity markers in a cross-sectional cohort and in a few patients that were followed prospectively. These data showcase the usefulness of measuring mRNA levels of key molecules in diagnosing and following patients with SLE.
    Clinical Immunology 12/2013; 150(2):192-200. · 3.77 Impact Factor
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    ABSTRACT: TCR-αβ+CD3+CD4-CD8- double negative T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Double negative T cells have been claimed to derive from CD8+ cells that down-regulate CD8 co-receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that double negative T cells have been documented in inflamed organs, suggests that they may contribute to disease expression and tissue damage. We recently linked the transcription factor cAMP responsive element modulator (CREM)α, which is expressed at increased levels in T cells from SLE patients and lupus prone MRL/lpr mice, with trans-repression of a region syntenic to the murine CD8b promoter. However, the exact molecular mechanisms that result in a stable silencing of both the CD8A and CD8B genes remain elusive. Here, we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase (DNMT)3a and histone methyltransferase G9a. Thus, we propose that CREMα is essential for the expansion of double negative T cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.
    Journal of Biological Chemistry 12/2013; · 4.65 Impact Factor
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    ABSTRACT: MicroRNA-155 (miR-155) regulates antibody responses and subsequent B-cell effector functions to exogenous antigens. However, the role of miR-155 in systemic autoimmunity is not known. Using the death receptor deficient (Fas(lpr)) lupus-prone mouse, we show here that ablation of miR-155 reduced autoantibody responses accompanied by a decrease in serum IgG but not IgM anti-dsDNA antibodies and a reduction of kidney inflammation. MiR-155 deletion in Fas(lpr) B cells restored the reduced SH2 domain-containing inositol 5'-phosphatase 1 to normal levels. In addition, coaggregation of the Fc γ receptor IIB with the B-cell receptor in miR-155(-/-)-Fas(lpr) B cells resulted in decreased ERK activation, proliferation, and production of switched antibodies compared with miR-155 sufficient Fas(lpr) B cells. Thus, by controlling the levels of SH2 domain-containing inositol 5'-phosphatase 1, miR-155 in part maintains an activation threshold that allows B cells to respond to antigens.
    Proceedings of the National Academy of Sciences 11/2013; · 9.74 Impact Factor
  • Source
    H K Wong, G M Kammer, G Dennis, G C Tsokos
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    ABSTRACT: TCR-ab+CD3+CD4-CD8- double negative T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and autoimmune lymphoproliferative syndrome. In both disorders, double negative T cells infiltrate tissues, induce immunoglobulin production and secrete pro-inflammatory cytokines. Double negative T cells derive from CD8+ T cells through down-regulation of CD8 surface co-receptors. However, the molecular mechanisms orchestrating this process remain unclear. Here, we demonstrate that transcription factor cAMP responsive element modulator (CREM)α, which is expressed at increased levels in T cells from SLE patients, contributes to transcriptional silencing of CD8A and CD8B. We provide first evidence that CREMα trans-represses a regulatory element 5 of the CD8B gene. Therefore, CREMα represents a promising candidate in the search for biomarkers and treatment options in diseases in which double negative T cells contribute to the pathogenesis.
    Journal of Biological Chemistry 09/2013; · 4.65 Impact Factor
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    ABSTRACT: Although a population of T cells with CD3ζ chain deficiency has been found in patients with systemic lupus erythematosus, rheumatoid arthritis, cancer, and infectious disease, the role of CD3ζ chain in the disease pathogenesis remains unknown. To understand the contribution of CD3ζ deficiency to the expression of organ injury, we have performed the following studies. We used CD3ζ-deficient mice to investigate the role of CD3ζ in the pathogenesis of organ tissue inflammation. We found that the CD3ζ(-/-) mice can spontaneously develop significant organ inflammation that can be accelerated following the administration of polyinosinic:polycytidylic acid or allogeneic cells (graft versus host). T cells from CD3ζ(-/-) mice display increased expression of the adhesion molecules CD44 and CCR2 and produce increased amounts of IFN-γ blockade, which mitigates tissue inflammation. Our results demonstrate that CD3ζ deficiency bestows T cells with the ability to infiltrate various tissues and instigate inflammation. Decreased CD3ζ expression noted in T cells from various diseases contributes independently to tissue inflammation and organ damage. Approaches to restore CD3ζ expression of the surface of T cells should be expected to mitigate tissue inflammation.
    The Journal of Immunology 08/2013; · 5.52 Impact Factor
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    ABSTRACT: Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects.
    Proceedings of the National Academy of Sciences 08/2013; · 9.74 Impact Factor
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    ABSTRACT: Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase involved in essential cellular functions. T cells from patients with systemic lupus erythematosus (SLE) express high levels of the catalytic subunit of PP2A (PP2Ac). A mouse over-expressing PP2Ac in T cells develops glomerulonephritis in an IL-17-dependent manner. Here, using microarray analyses, we demonstrate that increased expression of PP2Ac grants T cells the capacity to produce an array of pro-inflammatory effector molecules. Because IL-17 is important in the expression of glomerulonephritis, we studied the mechanism through which PP2Ac dysregulation facilitates its production. We report that PP2Ac is involved in the regulation of the Il17 locus by enhancing histone 3 (H3) acetylation through a mechanism that involves activation of interferon regulatory factor 4 (IRF4). Increased H3 acetylation of the Il17 locus, is shared between T cells of PP2Ac transgenic mice and patients with SLE. We propose that, by promoting the inflammatory capacity of T cells, PP2Ac dysregulation contributes to the pathogenesis of SLE.
    Journal of Biological Chemistry 08/2013; · 4.65 Impact Factor
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    ABSTRACT: DNA hypomethylation is a characteristic feature of SLE immune cells. Numerous reports have implicated the involvement of the mitogen-activated protein kinase kinase 1 (MEK)/extracellular signal-regulated kinase (ERK) pathway in the reduction of DNA methyltransferase (DNMT) expression, hence inducing the transcription of methylation-sensitive genes in SLE patients. However, the molecular mechanisms involved remain unclear. Here, we investigated whether the catalytic subunit of protein phosphatase 2A (PP2Ac) which is overexpressed in SLE T cells contributes to reduced DNA methylation. We show that both chemical suppression and siRNA silencing of PP2Ac in T cells results in sustained phosphorylation of MEK and ERK following stimulation with PMA and ionomycin. Furthermore, PP2Ac suppression resulted in increased DNMT enzymatic activity, DNA hypermethylation and decreased expression of methylation-sensitive genes. Similarly, in SLE T cells, suppression of PP2Ac resulted in increased MEK/ERK phosphorylation, enhanced DNMT1 expression and suppressed expression of the methylation-sensitive CD70 gene. Our results demonstrate that PP2A regulates DNA methylation by influencing the phosphorylation of MEK/ERK. We propose that enhanced PP2Ac in SLE T cells may dephosphorylate and activate the signaling pathway upstream of DNMT1, thus disturbing the tight control of methylation-sensitive genes, which are involved in SLE pathogenesis.
    Journal of Biological Chemistry 06/2013; · 4.65 Impact Factor
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    ABSTRACT: The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'-5' DNA exonuclease TREX1. In addition, genome-wide association studies have identified single-nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O-acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE.
    Nature Reviews Rheumatology 06/2013; · 9.75 Impact Factor
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    ABSTRACT: The costimulatory receptor Slamf6 partially controls lupus-related autoimmunity in congenic Sle1b mice; for instance, the presence of the protein isoform Slamf6-H1 in Sle1b.Slamf6-H1 mice mitigates disease. Here, we report that young Sle1b mice, but not Sle1b.Slamf6-H1 or B6 mice, contain a memory T-helper cell subset identified by ]mt]2-fold increase in expression of 17 genes, chief among which is Spp1, encoding the cytokine osteopontin (OPN). These T follicular helper (TFH) cells, including OPN(+) TFH cells, expand concomitantly with severity of the disease. By contrast, Sle1b.Slamf6-H1 or Sle1b.SAP(--) mice do not develop autoantibodies and the number of TFH cells is 5 times lower than in age-matched Sle1b mice. By comparing Sle1b and Sle1b.OPN(--) mice, we find that the lack of OPN expression impedes early autoantibody production. Furthermore, on the adoptive transfer of Sle1b.OPN(--) CD4(+) T cells into bm12 recipients autoantibody production and germinal center formation is reduced compared to recipients of Sle1b.OPN(+/+) CD4(+) T cells. We propose a model in which OPN provides a survival signal for a precursor TFH cell subset, which is a key factor in autoimmunity. Keszei, M., Detre, C., Castro, W., Magelky, E., O'Keeffe, M., Kis-Toth, K., Tsokos, G. C., Wang, N., Terhorst, C. Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor.
    The FASEB Journal 04/2013; · 5.70 Impact Factor

Publication Stats

8k Citations
2,172.25 Total Impact Points

Institutions

  • 2007–2014
    • Beth Israel Deaconess Medical Center
      • • Division of Rheumatology
      • • Department of Medicine
      Boston, Massachusetts, United States
    • Brigham and Women's Hospital
      • Department of Surgery
      Boston, MA, United States
    • University of Washington Seattle
      • Department of Immunology
      Seattle, WA, United States
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2007–2013
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2012
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
    • Boston Children's Hospital
      Boston, Massachusetts, United States
    • Brigham Young University - Provo Main Campus
      • Department of Microbiology and Molecular Biology
      Provo, UT, United States
  • 2011–2012
    • U.S. Army Institute of Surgical Research
      Houston, Texas, United States
  • 2010
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006–2009
    • University of Münster
      • • Institute of Immunology
      • • Institute of Experimental Pathology
      Münster, North Rhine-Westphalia, Germany
    • Yale University
      • School of Medicine
      New Haven, CT, United States
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1996–2009
    • Walter Reed Army Institute of Research
      • Center for Military Psychiatry and Neuroscience Research
      Silver Spring, Maryland, United States
  • 2006–2008
    • Kansas State University
      • Division of Biology
      Manhattan, KS, United States
  • 1992–2008
    • Walter Reed National Military Medical Center
      • • Department of Rheumatology
      • • Department of Surgery
      Washington, Washington, D.C., United States
  • 2006–2007
    • Complutense University of Madrid
      • Facultad de Medicina
      Madrid, Madrid, Spain
  • 2005–2007
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
    • National and Kapodistrian University of Athens
      • Division of Propedeutic Medicine I
      Athens, Attiki, Greece
    • University of Patras
      • Department of Internal Medicine
      Ríon, Greece
  • 1987–2007
    • Uniformed Services University of the Health Sciences
      • Department of Medicine
      Maryland, United States
  • 2002–2004
    • Wake Forest School of Medicine
      • • Department of Microbiology and Immunology
      • • Department of Internal Medicine
      Winston-Salem, NC, United States
  • 2003
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 1999
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
    • Henry M Jackson Foundation
      Maryland City, Maryland, United States
  • 1997
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1991–1994
    • Laiko Hospital
      Athínai, Attica, Greece
    • National Eye Institute
      Maryland, United States
    • Children's National Medical Center
      Washington, Washington, D.C., United States
  • 1974–1991
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 1990
    • State University of New York
      New York City, New York, United States
  • 1986–1990
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 1982
    • U.S. Food and Drug Administration
      Washington, Washington, D.C., United States