M B Brenner

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (282)3148.78 Total impact

  • Journal of immunology (Baltimore, Md. : 1950). 08/2014; 193(3):977-92.
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    ABSTRACT: Genome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862A, increased proliferative response (p = 4.75×10-8). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.
    PLoS Genetics 06/2014; 10(6):e1004404. · 8.52 Impact Factor
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    ABSTRACT: Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11-deficient mice and anti-Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow-derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11-knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti-Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.
    Arthritis & rheumatology (Hoboken, N.J.). 04/2014; 66(4):1010-21.
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    ABSTRACT: Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8(+) T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d(+) cancers, such as T-lymphoma.
    Cancer immunology research. 01/2014; 2(1):59-69.
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    ABSTRACT: Directional mesenchymal cell invasion in vivo is understood to be a stimulated event and to be regulated by cytokines, chemokines and types of extracellular matrix (ECM). Instead, by focusing on the cellular response to ECM stiffness, we found that soft ECM (low stiffness) itself is sufficient to prevent stable cell-to-cell adherens junction (AJ) formation, up-regulate MMP secretion, promote MMP activity and induce invadosome-like protrusion (ILP) formation. Consistently, similar ILP formation was also detected in a 3D directional invasion assay in soft matrix. Primary human fibroblasts spontaneously form ILPs in a very narrow range of ECM stiffness (0.1 ∼ 0.4 kPa) and such ILP formation is Src family kinase (SFK) dependent. In contrast, spontaneous ILP formation in malignant cancer cells and fibrosarcoma cells occurs across a much wider range of ECM stiffness, and these tumor cell ILPs are also more prominent at lower stiffness. These findings suggest that ECM softness is a natural stimulator for cellular invasiveness.
    Molecular biology of the cell 12/2013; · 5.98 Impact Factor
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    ABSTRACT: Defining and characterizing pathologies of the immune system requires precise and accurate quantification of abundances and functions of cellular subsets via cytometric studies. At this time, data analysis relies on manual gating, which is a major source of variability in large-scale studies. We devised an automated, user-guided method, X-Cyt, which specializes in rapidly and robustly identifying targeted populations of interest in large data sets. We first applied X-Cyt to quantify CD4(+) effector and central memory T cells in 236 samples, demonstrating high concordance with manual analysis (r = 0.91 and 0.95, respectively) and superior performance to other available methods. We then quantified the rare mucosal associated invariant T cell population in 35 samples, achieving manual concordance of 0.98. Finally we characterized the population dynamics of invariant natural killer T (iNKT) cells, a particularly rare peripheral lymphocyte, in 110 individuals by assaying 19 markers. We demonstrated that although iNKT cell numbers and marker expression are highly variable in the population, iNKT abundance correlates with sex and age, and the expression of phenotypic and functional markers correlates closely with CD4 expression.
    Proceedings of the National Academy of Sciences 11/2013; · 9.81 Impact Factor
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    ABSTRACT: Natural Killer (NK) lymphocytes contain lysosome-related organelles (LROs) known as lytic granules that upon formation of immunological synapse (IS) with the target cell, polarize toward the IS to deliver their contents to the target cell membrane. Here, we have identified small GTP-binding protein, Arl8b, as a critical factor required for NK-cell mediated cytotoxicity. Our findings indicate that Arl8b drives the polarization of lytic granules and MTOC toward the immune synapse between effector NK lymphocytes and target cells. Using a GST-pulldown approach, we identified KIF5B (the heavy chain of kinesin-1) as an interaction partner of Arl8b from NK cell lysates. Previous studies have shown interaction between kinesin-1 and Arl8b is mediated by SifA and kinesin-interacting protein (SKIP) and the tripartite complex drives the anterograde movement of lysosomes. Silencing of both KIF5B and SKIP in NK cells, similar to Arl8b, led to a failure of MTOC-lytic granule polarization to the immune synapse suggesting that Arl8b and kinesin-1 together control this critical step in NK cell cytotoxicity.
    Molecular biology of the cell 10/2013; · 5.98 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
  • Patrick J Brennan, Manfred Brigl, Michael B Brenner
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    ABSTRACT: Invariant natural killer T (iNKT) cells exist in a 'poised effector' state, which enables them to rapidly produce cytokines following activation. Using a nearly monospecific T cell receptor, they recognize self and foreign lipid antigens presented by CD1d in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses. In this Review, we discuss recent advances in our understanding of the innate-like mechanisms underlying iNKT cell activation and describe how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iNKT cells in health and disease.
    Nature Reviews Immunology 01/2013; · 32.25 Impact Factor
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    ABSTRACT: CD1d-restricted natural killer T (NKT) cells include two major subgroups. The most widely studied are Vα14Jα18(+) invariant NKT (iNKT) cells that recognize the prototypical α-galactosylceramide antigen, whereas the other major group uses diverse T-cell receptor (TCR) α-and β-chains, does not recognize α-galactosylceramide, and is referred to as diverse NKT (dNKT) cells. dNKT cells play important roles during infection and autoimmunity, but the antigens they recognize remain poorly understood. Here, we identified phosphatidylglycerol (PG), diphosphatidylglycerol (DPG, or cardiolipin), and phosphatidylinositol from Mycobacterium tuberculosis or Corynebacterium glutamicum as microbial antigens that stimulated various dNKT, but not iNKT, hybridomas. dNKT hybridomas showed distinct reactivities for diverse antigens. Stimulation of dNKT hybridomas by microbial PG was independent of Toll-like receptor-mediated signaling by antigen-presenting cells and required lipid uptake and/or processing. Furthermore, microbial PG bound to CD1d molecules and plate-bound PG/CD1d complexes stimulated dNKT hybridomas, indicating direct recognition by the dNKT cell TCR. Interestingly, despite structural differences in acyl chain composition between microbial and mammalian PG and DPG, lipids from both sources stimulated dNKT hybridomas, suggesting that presentation of microbial lipids and enhanced availability of stimulatory self-lipids may both contribute to dNKT cell activation during infection.
    Proceedings of the National Academy of Sciences 01/2013; · 9.81 Impact Factor
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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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    ABSTRACT: The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.
    Nature Immunology 01/2013; 14(6):619-632. · 26.20 Impact Factor
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    Proc. Natl. Acad. Sci. U.S.A. 01/2013; 110(35):14324-14329.
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    ABSTRACT: The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.
    Nature Immunology 01/2013; 14(6):633-643. · 26.20 Impact Factor
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    ABSTRACT: Isoglobotrihexosylceramide (iGb3) has been identified as a potent CD1d-presented self-antigen for mouse iNKT cells. The role of iGb3 in humans remains unresolved, however, as there have been conflicting reports about iGb3-dependent human iNKT-cell activation, and humans lack iGb3 synthase, a key enzyme for iGb3 synthesis. Given the importance of human immune responses, we conducted a human-mouse cross-species analysis of iNKT-cell activation by iGb3-CD1d. Here we show that human and mouse iNKT cells were both able to recognise iGb3 presented by mouse CD1d (mCD1d), but not human CD1d (hCD1d), as iGb3-hCD1d was unable to support cognate interactions with the iNKT-cell TCRs tested in this study. The structural basis for this discrepancy was identified as a single amino acid variation between hCD1d and mCD1d, a glycine-to-tryptophan modification within the alpha2-helix that prevents flattening of the iGb3 headgroup upon TCR ligation. Mutation of the human residue, Trp153, to the mouse ortholog, Gly155, therefore allowed iGb3-hCD1d to stimulate human iNKT cells. In conclusion, our data indicate that iGb3 is unlikely to be a major antigen in human iNKT-cell biology.
    European Journal of Immunology 12/2012; · 4.97 Impact Factor
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    ABSTRACT: Intracellular recycling pathways play critical roles in internalizing membrane and fluid phase cargo and in balancing the inflow and outflow of membrane and cell surface molecules. To identify proteins involved in the regulation of endocytic recycling, we used an shRNA trafficking library and screened for changes in the surface expression of CD1a antigen-presenting molecules that follow an endocytic recycling route. We found that silencing of the ADP-ribosylation factor (Arf)-like small GTPase Arl13b led to a decrease in CD1a surface expression, diminished CD1a function, and delayed CD1a recycling, suggesting that Arl13b is involved in the regulation of endocytic recycling traffic. Arl13b appears to be required for the major route of endocytic trafficking, causing clustering of early endosomes and leading to the accumulation of endocytic cargo. Moreover, Arl13b colocalized with markers of the endocytic recycling pathway followed by CD1a, namely Arf6 and Rab22a. We also detected an interaction between Arl13b and the actin cytoskeleton. Arl13b was previously implicated in cilia formation and function. Our present results indicate a previously unidentified role for Arl13b in endocytic recycling traffic and suggest a link between Arl13b function and the actin cytoskeleton.
    Proceedings of the National Academy of Sciences 12/2012; · 9.81 Impact Factor
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    ABSTRACT: Invariant natural killer T cells (iNKT cells) are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled gene expression in iNKT cells during ontogeny and in peripheral subsets as part of the Immunological Genome Project. High-resolution comparative transcriptional analyses defined developmental and subset-specific programs of gene expression by iNKT cells. In addition, we found that iNKT cells shared an extensive transcriptional program with NK cells, similar in magnitude to that shared with major histocompatibility complex (MHC)-restricted T cells. Notably, the program shared by NK cells and iNKT cells also operated constitutively in γδ T cells and in adaptive T cells after activation. Together our findings highlight a core effector program regulated distinctly in innate and adaptive lymphocytes.
    Nature Immunology 12/2012; · 26.20 Impact Factor
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    ABSTRACT: We attempted to find new proteins involved in the regulation of the endocytic recycling pathway used by CD1a, a MHC Class I-like lipid antigen-presenting molecule that follows an endocytic recycling pathway similar to that used by MHC Class I and other cargo internalized independently of clathrin. For that, a shRNA library comprising the main families of proteins known to be involved in membrane trafficking was used to screen HeLa:CD1a cells for changes in CD1a surface expression that could reflect intracellular trafficking defects. Our finding that Arl13b silencing leads to a decrease in CD1a surface expression and function, as well as a delay in CD1a recycling, suggests that this ciliary protein is involved in the regulation of endocytic recycling trafficking. Moreover, Arl13b silencing caused the clustering of early endosomes and the accumulation in this organelle of recycling cargo, such as transferrin, and also cargo destined for late endosomes and lysosomes, such as dextran. We also found Arl13b to colocalize with Arf6 mutants that lead to an accumulation of clathrin-independent recycling cargo and in recycling tubules labeled by Rab22a. Together, these results indicate that Arl13b regulates a sorting step from the early/sorting endosome. Surprisingly, we found Arl13b to colocalize with actin filaments and to immunoprecipitate with actin, which brings mechanistic insight into the function of this Arl protein. Thus, our results indicate a previously unidentified role for Arl13b in the endocytic recycling pathway and suggest a link between Arl13b function and the actin cytoskeleton.
    BMC cilia. 11/2012; 1(Suppl 1):O7.
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    ABSTRACT: Although the field has a long collaborative tradition, immunology has made less use than genetics of 'consortium biology', wherein groups of investigators together tackle large integrated questions or problems. However, immunology is naturally suited to large-scale integrative and systems-level approaches, owing to the multicellular and adaptive nature of the cells it encompasses. Here, we discuss the value and drawbacks of this organization of research, in the context of the long-running 'big science' debate, and consider the opportunities that may exist for the immunology community. We position this analysis in light of our own experience, both positive and negative, as participants of the Immunological Genome Project.
    Nature Reviews Immunology 10/2012; · 32.25 Impact Factor
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    ABSTRACT: We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and FcγR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-α, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells.
    Nature Immunology 09/2012; 13(11):1118-1128. · 26.20 Impact Factor

Publication Stats

20k Citations
3,148.78 Total Impact Points

Institutions

  • 1992–2014
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Rheumatology, Immunology, and Allergy
      Boston, Massachusetts, United States
  • 2013
    • University of California, San Diego
      • Division of Biological Sciences
      San Diego, CA, United States
  • 2012
    • Asthma Allergy & Immunology Institute
      Southfield, Michigan, United States
  • 1988–2012
    • Harvard Medical School
      • • Department of Medicine
      • • Division of Medical Sciences
      Boston, Massachusetts, United States
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 1989–2009
    • University of California, Los Angeles
      • Division of Dermatology
      Los Angeles, CA, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, MA, United States
  • 2007
    • Kyoto University
      • Institute for Virus Research
      Kyoto, Kyoto-fu, Japan
  • 2003–2007
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands
  • 2004
    • Nippon Medical School
      • Department of Microbiology and Immunology
      Tokyo, Tokyo-to, Japan
  • 2002
    • Joslin Diabetes Center
      • Section on Immunobiology
      Boston, MA, United States
  • 2000
    • University of Iowa
      • Department of Internal Medicine
      Iowa City, IA, United States
    • Lund University
      Lund, Skåne, Sweden
  • 1998
    • Albert Einstein College of Medicine
      • Department of Microbiology & Immunology
      New York City, NY, United States
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 1996
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, MA, United States
  • 1995
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1987–1992
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • University of Southern California
      • Department of Pathology
      Los Angeles, CA, United States