Diane Mathis

Harvard Medical School, Boston, Massachusetts, United States

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Publications (346)4556.47 Total impact

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    ABSTRACT: FOXP3(+) regulatory T (Treg) cells enforce immune self-tolerance and homeostasis, and variation in some aspects of Treg function may contribute to human autoimmune diseases. Here, we analyzed population-level Treg variability by performing genome-wide expression profiling of CD4(+) Treg and conventional CD4(+) T (Tconv) cells from 168 donors, healthy or with established type-1 diabetes (T1D) or type-2 diabetes (T2D), in relation to genetic and immunologic screening. There was a range of variability in Treg signature transcripts, some almost invariant, others more variable, with more extensive variability for genes that control effector function (ENTPD1, FCRL1) than for lineage-specification factors like FOXP3 or IKZF2. Network analysis of Treg signature genes identified coregulated clusters that respond similarly to genetic and environmental variation in Treg and Tconv cells, denoting qualitative differences in otherwise shared regulatory circuits whereas other clusters are coregulated in Treg, but not Tconv, cells, suggesting Treg-specific regulation of genes like CTLA4 or DUSP4. Dense genotyping identified 110 local genetic variants (cis-expression quantitative trait loci), some of which are specifically active in Treg, but not Tconv, cells. The Treg signature became sharper with age and with increasing body-mass index, suggesting a tuning of Treg function with repertoire selection and/or chronic inflammation. Some Treg signature transcripts correlated with FOXP3 mRNA and/or protein, suggesting transcriptional or posttranslational regulatory relationships. Although no single transcript showed significant association to diabetes, overall expression of the Treg signature was subtly perturbed in T1D, but not T2D, patients.
    Proceedings of the National Academy of Sciences 03/2014; · 9.74 Impact Factor
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    ABSTRACT: A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or β3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis. They also showed altered fat distribution with markedly increased subcutaneous adiposity. Subcutaneous adipose tissue in mutant mice acquired many key properties of visceral fat, including decreased thermogenic and increased inflammatory gene expression and increased macrophage accumulation. Transplantation of subcutaneous fat into mice with diet-induced obesity showed a loss of metabolic benefit when tissues were derived from PRDM16 mutant animals. These findings indicate that PRDM16 and beige adipocytes are required for the "browning" of white fat and the healthful effects of subcutaneous adipose tissue.
    Cell 01/2014; 156(1-2):304-16. · 31.96 Impact Factor
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    ABSTRACT: Aire induces the expression of a large set of autoantigen genes in the thymus, driving immunological tolerance in maturing T cells. To determine the full spectrum of molecular mechanisms underlying the Aire transactivation function, we screened an AIRE-dependent gene-expression system with a genome-scale lentiviral shRNA library, targeting factors associated with chromatin architecture/function, transcription, and mRNA processing. Fifty-one functional allies were identified, with a preponderance of factors that impact transcriptional elongation compared with initiation, in particular members of the positive transcription elongation factor b (P-TEFb) involved in the release of "paused" RNA polymerases (CCNT2 and HEXIM1); mRNA processing and polyadenylation factors were also highlighted (HNRNPL/F, SFRS1, SFRS3, and CLP1). Aire's functional allies were validated on transfected and endogenous target genes, including the generation of lentigenic knockdown (KD) mice. We uncovered the effect of the splicing factor Hnrnpl on Aire-induced transcription. Transcripts sensitive to the P-TEFb inhibitor flavopiridol were reduced by Hnrnpl knockdown in thymic epithelial cells, independently of their dependence on Aire, therefore indicating a general effect of Hnrnpl on RNA elongation. This conclusion was substantiated by demonstration of HNRNPL interactions with P-TEFb components (CDK9, CCNT2, HEXIM1, and the small 7SK RNA). Aire-containing complexes include 7SK RNA, the latter interaction disrupted by HNRNPL knockdown, suggesting that HNRNPL may partake in delivering inactive P-TEFb to Aire. Thus, these results indicate that mRNA processing factors cooperate with Aire to release stalled polymerases and to activate ectopic expression of autoantigen genes in the thymus.
    Proceedings of the National Academy of Sciences 01/2014; · 9.74 Impact Factor
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    ABSTRACT: The ability to reliably identify pancreatic β-cells would have far reaching implications for a greater understanding of β-cell biology, measurement of β-cell mass in diabetes, islet transplantation, and drug development. The glucagon-like peptide-1 receptor (GLP1R) is highly expressed on the surface of insulin producing pancreatic β-cells. Using systematic modifications of the GLP1R ligand, exendin-4, we screened over 25 compounds and identified a palette of fluorescent exendin-4 with high GLP1R binding affinity. We show considerable differences in affinity, as well as utility of the top candidates for flow cytometry and microscopy of β-cells. Some of the developed compounds should be particularly useful for basic and translational β-cell research.
    Bioconjugate Chemistry 12/2013; · 4.58 Impact Factor
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    ABSTRACT: Long recognized to be potent suppressors of immune responses, Foxp3(+)CD4(+) regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
    Cell 12/2013; 155(6):1282-95. · 31.96 Impact Factor
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    ABSTRACT: Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA's actions were dependent on ATF6 and were lost in mice with β cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.
    Science translational medicine 11/2013; 5(211):211ra156. · 10.76 Impact Factor
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    ABSTRACT: Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells leading to insulin deficiency. While infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells which positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4(+) and CD8(+) T-cells, but not B-cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose, circulating insulin or by modulating apoptosis. Complementary to our in vivo approach co-culture of diabetogenic CD4(+) and CD8(+) T-cells with NOD.RAG1(-/-) islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokine/chemokines (IL-2, IL-6, IL-10, MIP-1α and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.
    Diabetes 10/2013; · 7.90 Impact Factor
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    ABSTRACT: Both Foxp3(+)CD4(+) regulatory T cells (Treg cells) and local immune responses in nonlymphoid tissues have long been recognized as important elements of a well-orchestrated immune system, but only recently have these two fields of study begun to intersect. There is growing evidence that Treg cells are present in various nonlymphoid tissues in health and disease, that they have a unique phenotype and that their functions go beyond the classical modulation of immune responses. Thus, tissue Treg cells might add yet another level to classification of the Treg cell compartment into functional and/or phenotypic subtypes. In this Review, we summarize recent findings in this new field, discussing knowns and unknowns about the origin, phenotype, function and memory of nonlymphoid tissue-resident Treg cells.
    Nature Immunology 10/2013; 14(10):1007-13. · 26.20 Impact Factor
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    ABSTRACT: Several clinical trials have shown anti-CD3 treatment to be a promising therapy for autoimmune diabetes, but its mechanism of action remains unclear. Foxp3(+) regulatory T cells (Tregs) are likely to be involved, but through unknown mechanistic pathways. We profiled the transcriptional consequences in CD4(+) Tregs and conventional T cells (Tconvs) in the first hours and days after anti-CD3 treatment of NOD mice. Anti-CD3 treatment led to a transient transcriptional response, terminating faster than most Ag-induced responses. Most transcripts were similarly induced in Tregs and Tconvs, but several were differential, in particular, those encoding the IL-7R and transcription factors Id2/3 and Gfi1, upregulated in Tregs but repressed in Tconvs. Because IL-7R was a plausible candidate for driving the homeostatic response of Tregs to anti-CD3, we tested its relevance by supplementation of anti-CD3 treatment with IL-7/anti-IL-7 complexes. Although ineffective alone, IL-7 significantly improved the rate of remission induced by anti-CD3. Four anti-human CD3 mAbs exhibited the same differential effect on IL-7R expression in human as in mouse cells, suggesting that the mechanism also underlies therapeutic effect in human cells, and perhaps a rationale for testing a combination of anti-CD3 and IL-7 for the treatment of recent-onset human type 1 diabetes. Thus, systems-level analysis of the response to anti-CD3 in the early phase of the treatment demonstrates different responses in Tregs and Tconvs, and provides new leads to a mechanistic understanding of its mechanism of action in reverting recent-onset diabetes.
    The Journal of Immunology 08/2013; · 5.52 Impact Factor
  • Diane Mathis
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    ABSTRACT: Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme.
    Cell metabolism 06/2013; 17(6):851-9. · 17.35 Impact Factor
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    ABSTRACT: Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK-T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4(+) T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4(+) T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets.
    Journal of Experimental Medicine 05/2013; · 13.21 Impact Factor
  • Nature Immunology 03/2013; 14(4):307-308. · 26.20 Impact Factor
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    ABSTRACT: After infection, many factors coordinate the population expansion and differentiation of CD8(+) effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8(+) T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8(+) effector cells. Long-lived memory CD8(+) cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8(+) effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8(+) T cell immunity.
    Nature Immunology 02/2013; · 26.20 Impact Factor
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    ABSTRACT: Type 2 diabetes is now a worldwide epidemic, strongly correlated with an elevated incidence of obesity. Obesity-associated adipose tissue inflammation is a major cause of the decreased insulin sensitivity seen in type 2 diabetes. Recent studies have shed light on the cross-talk between the immune system and organismal metabolism. This review discusses the connection between inflammation in adipose tissue and systemic insulin resistance, focusing on the roles of innate and adaptive immune cell subsets in the pathogenesis of this metabolic disease.
    Seminars in Immunology 01/2013; · 5.93 Impact Factor
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    ABSTRACT: Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire's nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire's two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.
    Proceedings of the National Academy of Sciences 01/2013; · 9.74 Impact Factor
  • Proc. Natl. Acad. Sci. U.S.A. 01/2013; 110(35):14324-14329.
  • Nat. Immunol. 01/2013; 14(6):619-632.
  • Nat. Immunol. 01/2013; 14(6):633-643.
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    ABSTRACT: How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of high-mobility group (HMG) box transcription factors, SOX4, SOX13, TCF1, and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46(+) ILCs and restrained cytokine production by lymphoid tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins.
    Immunity 01/2013; 38(4):681-693. · 19.80 Impact Factor
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    Diane Mathis
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    ABSTRACT: The gut microbiota of patients recently diagnosed with rheumatoid arthritis is enriched in microbes belonging to the Prevotella genus.
    eLife. 01/2013; 2.

Publication Stats

22k Citations
4,556.47 Total Impact Points


  • 2000–2014
    • Harvard Medical School
      • • Division of Immunology
      • • Department of Pathology
      Boston, Massachusetts, United States
    • Transgene
      Illkirch, Alsace, France
  • 2013
    • University of California, San Diego
      • Division of Biological Sciences
      San Diego, CA, United States
  • 2012
    • Asthma Allergy & Immunology Institute
      Southfield, Michigan, United States
  • 2009–2012
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
  • 2011
    • Massachusetts General Hospital
      • Center for Systems Biology
      Boston, MA, United States
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002–2011
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2010
    • University of Oxford
      • Wellcome Trust Centre for Human Genetics
      Oxford, ENG, United Kingdom
  • 2001–2010
    • Joslin Diabetes Center
      • Section on Immunobiology
      Boston, MA, United States
    • University of Porto
      • Institute for Molecular and Cell Biology
      Oporto, Porto, Portugal
  • 2006
    • Dokkyo Medical University
      • Department of Hematology
      Tochigi, Tochigi-ken, Japan
  • 1987–2006
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France
  • 1988–2000
    • French Institute of Health and Medical Research
      • Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) U964
      Paris, Ile-de-France, France
  • 1998
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1988–1998
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1996
    • University of Strasbourg
      • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasbourg, Alsace, France
  • 1994
    • Institut de biologie moléculaire des plantes, Strasbourg
      Strasburg, Alsace, France
  • 1991
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom
  • 1989
    • Johannes Gutenberg-Universität Mainz
      • Institute for Immunology
      Mainz, Rhineland-Palatinate, Germany
  • 1988–1989
    • Erasmus Universiteit Rotterdam
      • Department of Immunology
      Rotterdam, South Holland, Netherlands