Immunology Faculty Member - Michael Brenner, MD

Michael Brenner, MD

Brigham and Women's Hospital
BTM, 6th Floor, Room 6002T
60 Fenwood Road
Boston, MA 02115
Tel: 617-525-1000
Fax: 617-525-1001
Email: mbrenner@research.bwh.harvard.edu
Lab Members: 4 graduate students, 5 postdoctoral fellows, 2 junior faculty



Autoimmune Disease Deconstruction:

New pathological T cells
: We have implemented a disease deconstruction pipeline using single cell technologies applied to inflamed tissues. In studies of rheumatoid arthritis (RA), we carry out synovial tissue biopsies along with paired blood analyses and clinical correlations. We are using mass cytometry (CyTOF) for deep immunophenotyping of blood and have developed CyTOF panels for autoimmune tissues. With single cell RNA sequencing applied to biopsies, we obtain transcriptional data on both the inflammatory cells eliciting damage and the tissue parenchymal cell responses. Recently, using a CyTOF screen to query T cells, we identified a new population of T helper cells that we have named T peripheral helper (Tph) cells, to distinguish them from T follicular helper (Tfh) cells (Rao et al Nature 2017; 542:110-114). Tph cells are found in leukocyte aggregates and tertiary lymphoid tissue in chronic inflammatory reactions in peripheral tissues where they drive autoantibody production. They express high levels of PD1 and ICOS like Tfh cells, but instead of expressing CXCR5 and localizing in lymph node germinal centers, they express CCR2 and home to peripheral tissues where they secrete CXCL13, the ligand to CXCR5, and drive T-B clusters and provide help to B cells in autoimmune lesions. We are determining if these pathological T cells drive autoantibody production across autoimmune diseases in general. Targeting Tph cells may provide a powerful step forward in therapeutics by targeting only the pathological T cells and avoiding blunt deletion or blocking of T cells in general.
Stromal cells that drive inflammation in tissues: We are studying the role of stromal fibroblasts in autoimmune disease. In recent years, fibroblastic stromal cells have been found to play key roles in regulating immune responses in lymph nodes and tumors. We have found that in inflamed peripheral tissues, stromal fibroblasts function as the main inflammatory cells that secrete IL-6 and chemokines that recruit and sustain chronic inflammation. No drugs that target fibroblasts are yet approved as medical treatments, but we have identified an approach to target activated inflammatory fibroblasts and abate chronic synovial inflammation in mouse models of inflammatory arthritis. We found that mesenchymal cadherins, important adhesion molecules in tissue morphogenesis are characteristic of activated fibroblasts in tissues and regulate their inflammatory behavior (Chang et al. PNAS 2011; 108:8402-8407). When fibroblast cadherin-11 is deleted or blocked, synovial lining formation is attenuated and the inflammatory response in mouse models of inflammatory arthritis resolves (Lee et al. Science 2007; 315:1006-1010).
Signal Specific Inflammatory Modules in stromal cells determine the inflammatory effector functions of fibroblasts. Recently, we defined signal specific gene experession modules in fibroblasts that regulate their secretion of of IL-6 in chronically inflamed tissues in RA. IL-6 is part of an extensive program of inflammatory factors and transcription factor regulators that are co-expressed as an inflammatory module dependent upon an autocrine feedback loop mediated by cell surface IL-6 receptor family members, including IL-6R, oncostatin M receptor and LIF receptor (Nguyen et al. Immunity 2017; 46:220-232). We are now examining the expression of these inflammatory modules in RA and other autoimmune tissues that implicate fibroblasts as key regulators of peripheral tissue inflammation.

Innate T Cells:

Our laboratory defined the system of CD1 restricted lipid antigen presentation to T cells (Beckman et al. Nature 1994; 372:691-694). CD1 molecules (CD1a, b, c and d) are MHC class I-like proteins that contain hydrophobic channels that bind the acyl chain tails of lipid antigens. This allows lipids to bind to CD1 antigen presenting molecules analogous to peptide binding to MHC. The genes encoding the CD1a, b, c and d molecules represent a distinct lineage of antigen presenting elements that open T cell recognition to the universe of lipid containing self and foreign antigens. These antigens include glycolipids (including sphingolipids, diacylglycerols), lipopeptides and fatty acids that are found in the cell walls of microbes or are self-lipids antigens in mammalian cells. CD1 restricted iNKT cells can secrete Th1, Th2 or Th17 cytokines and mediate host defense against microbial infections or immunopathology. CD1d activated iNKT cells.
iNKT cells transactivate other leukocytes: iNKT cells often function as cellular adjuvants transactivating other leukocytes. iNKT cells are early sensors of danger and microbial infection. We have focused on how iNKT cells transactivate DCs which leads to DC instruction and maturation. The activated DC then presents self lipid antigens that drive even stronger iNKT cell activation in a cycle. (Cohen et al. Cell Host Microbe 2011; 10:437-450) (Brigl et al. J Exp Med. 2011; 208:1163-1177). We are now studying how iNKT cells regulate DC transactivation and production of IL-1 and IL-18 via inflammasome and non inflammasome mechanisms.
Regulatory innate iNKT cells: Recently, we identified a distinct population of iNKT cells that fuction as regulatory T cells. They provide homeostatic regulation to prevent inflammation in adipose tissue. When inflammation in adipose tissue occurs, it leads to insulin resistance and type 2 diabetes. We found that adipose tissue iNKT cells regulate the regulators. Namely, iNKT cells in adipose tissue are the prime source of IL-2 that is required for Treg expansion and function. When iNKT cells are deficient, Treg cell numbers are profoundly reduced in adipose tissue and adipose inflammation, diabetes and obesity result. The important role of innate T cells in adipose tissue is underscored by our finding that they also regulate thermogenesis to set body temperatue. When iNKT cells are absent, body termperature and metabolic rate are reduced altering energy utilization. When stimulated, iNKT cells drive the uncoupling of oxidative phosphorylation from ATP generation resulting in heat production and browning of white fat (Lynch et al. Nat Immunol. 2015; 16:85-95) (Lynch et al. Cell Metab. 2016; 24:510-519).

Last Update: 10/17/2017



Last Update: 10/24/2017



Publications

Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F, Teslovich NC, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Lee YC, Todd DJ, Bykerk VP, Goodman SM, Pernis AB, Ivashkiv LB, Karlson EW, Nigrovic PA, Filer A, Buckley CD, Lederer JA, Raychaudhuri S, Brenner MB. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 2017; 542:110-114.

Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, Leon L, Lee SY, Lee DM,
Brenner MB. Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci USA 2011; 108:8402-8407.

Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GFM, Chisaka O, Takeichi M,
Brenner MB. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007; 315:1006-1010.

Nguyen HN, Noss EH, Mizoguchi F, Huppertz C, Wei KS, Watts GF,
Brenner MB. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 2017; 46:220-232.

Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST,
Brenner MB. Recognition of a lipid antigen by CD1-restricted + T cells. Nature 1994; 372:691-694.

Cohen NR, Tatituri RVV, Rivera A, Watts GFM, Kim EY, Chiba A, Fuchs BB, Mylonakis E, Besra GS, Levitz SM, Brigl M,
Brenner MB. Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi. Cell Host Microbe 2011; 10:437-450.

Brigl M, Tattituri RVV, Watts GFM, Bhowruth V, Leadbetter EA, Barton N, Cohen NR, Hsu FF, Besra GS,
Brenner MB. Innate and cytokine-dirven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med. 2011; 208:1163-1177.

Lynch L, Michelet X, Zhang S, Brennan PJ, Moseman A, Lester C, Besra G, Vomhof-Dekrey EE, Tighe M, Koay H-F, Godfrey DI, Leadbetter EA, Sant'Angelo DB, von Andrian U, 
Brenner MB. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of Treg cells and macrophages in adipose tissue. Nat Immunol.  2015; 16:85-95.

Lynch L, Hogan AE, Duquette D, Lester C, Banks A, LeClair K, Cohen DE, Ghosh A, Lu B, Corrigan M, Stevanovic D, Maratos-Flier E, Drucker DJ, O'Shea D,
Brenner M. iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy. Cell Metab. 2016 24:510-519.



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of Harvard College