Michael Barry Brenner

Autoimmune Disease Deconstruction:

We have implemented a disease deconstruction pipeline using single cell and spatial technologies applied to inflamed tissues in humans to discover new cell types, cell states and pathways that mediate autoimmune disease. We then use in vitro organoids, other reductionist approaches, and gmouse models to define mechanisms and therapeutic insights for the new pathways and cell states. By shifting between humans and mice, our studies unravel the most relevant autoimmune and inflammatory abnormalities in vivo and then interrogate them in experimental systems. Over the past few years, we have identified new pathogenic T cell populations, macrophage states, and stromal cell subsets that drive pathology in autoimmune disease.  Recently, we identified a new pathway of complement activation. Below are several of these examples.

New pathological T helper cell subset (Tph cells) drives autoantibody production:

We carried out mass cytometry (CyTOF) and single cell RNA sequencing with unbiased cl

Autoimmune Disease Deconstruction:

We have implemented a disease deconstruction pipeline using single cell and spatial technologies applied to inflamed tissues in humans to discover new cell types, cell states and pathways that mediate autoimmune disease. We then use in vitro organoids, other reductionist approaches, and mouse models to define mechanisms and therapeutic insights for the new pathways and cell states. By shifting between humans and mice, our studies unravel the most relevant autoimmune and inflammatory abnormalities in vivo and then interrogate them in experimental systems. Over the past few years, we have identified new pathogenic T cell populations, macrophage states, and stromal cell subsets that drive pathology in autoimmune disease.  Recently, we identified a new pathway of complement activation. Below are several of these examples.

New pathological T helper cell subset (Tph cells) drives autoantibody production:

We carried out mass cytometry (CyTOF) and single cell RNA sequencing with unbiased clustering of synovial tissue cells in rheumatoid arthritis (RA). Using these approaches, 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. Tph cells are found in leukocyte aggregates in chronically inflamed peripheral tissues where they drive extrafollicular B cell differentiation and autoantibody production. Tph cells express high levels of PD1 and ICOS, but unlike Tfh cells they have low expression of Bcl6 and 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 for CXCR5 and IL-21 to provide B cell help and plasma cell differentiation in peripheral autoimmune lesions. Figure below shows Tfh cells (upper) and Tph cells (lower) panels.

Since our initial studies, Tph cells have been found to be expanded in a range of inflammatory diseases including lupus, autoimmune hepatitis, Celiac disease, juvenile idiopathic arthritis (JIA) and other conditions where autoantibodies are present.

 

 

 

a) 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.  PMCID:  PMC534932

Granzyme K (GzmK) CD8 T cells are the dominant tissue CD8 T cell phenotype in inflamed tissues.  They drive a newly identified pathway of tissue complement activation.

Most previous studies on CD8 T cells have focused on the role of CTL (cytolytic T lymphocytes) expressing granzyme B that cleaves caspases and kills target cells. However, using scRNA-seq of inflamed tissues, we found that the major phenotype of tissue CD8 T cells in humans expressed high levels of granzyme K (GzmK) either without or with only low levels of GzmB. In fact, GzmK CD8 T cells dominate in the inflamed tissues not only in RA, but also in Crohn’s Disease and ulcerative colitis gut, lupus nephritis kidney and other autoimmune diseases.  This surprising finding led us to ask what GzmK+ CD8 T cells do.  Remarkably, we found that GzmK mediates a new pathway of complement activation.  GzmK cleaves both complement factor 4 and factor 2 to generate an active C3 convertase (C4b2a) which cleaves factor 3 to yield C3a (the anaphylatoxin) and CD3b (the opsonin) with consequent formation of a C5 convertase and activation of the downstream complement mediated inflammation (C5a and MAC).  In inflamed tissues, stromal fibroblasts produce large amounts of C2, C3 and C4 which are the major source of complement produce locally and acted on by GzmK.  This represents a tissue focused process that differs from the previously known classical, alternative or lectin pathways of complement activation.  In contrast to serum complement derived from the liver, here

complement is produced locally in tissues; and further, compared to the proteases that initiate the classical pathway (C1r, C1s), the alternative pathway (CFB) or the lectin pathway (MASP1, MASP2), it is lymphocyte-derived GzmK that is the protease that drives this new pathway of complement activation.

 

a) Jonsson AH, Zhang F, Dunlap G, Gomez-Rivas E, Watts GFM, Faust HJ, Vijay Rupani K, Mears JR, Meednu N, Wang R, Keras G, Coblyn JS, Massarotti EM, Todd DJ, Anolik H, McDavid A, Accelerating Medicines Partnership (AMP): RA/SLE Network, Wei K, Rao DA, Raychaudhuri S, Brenner MB. Granzyme K+ CD8 T cells form a core population in inflamed human tissue.  Science Translational Medicine 2022; PMID: 35704599 DOI: 10.1126/scitranslmed.abo0686

b) Donado C, Jonsson AH, Theisen E, Zhang F, Nathan A, Rupani KV, Jones D, Accelerating Medicines Partnership RA/SLE Network, Raychaudhuri S, Dwyer DF, and Brenner MB.  Granzyme K drives a newly-intentified pathway of complement activation. bioRxiv preprint doi: https://doi.org/10.1101/2024.05.22.595315

Super-activated macrophages:

IFN SLAMF7

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of pathological macrophage activation, we analyzed RNA-seq data from human autoimmune disease tissues and identified SLAMF7 as a receptor associated with a super-activated macrophage state in rheumatoid arthritis. This occurs by a two-step process in which IFNg exposure upregulates SLAMF7 expression following which homotypic engagement of SLAMF7 by SLAMF7 on other cells, drives an exuberant wave of inflammatory cytokine expression exceeding that of macrophages activated by TNF, IFN gamma, TLR and other agonists.  Figure (left) shows heat map of gene expression from cultured macrophages after IFN gamma stimulation alone versus IFN gamma and SLAMF7 stimulation (expression of multiple chemokines, cytokines, growth factors expressed at the highest levels detected following any type of activation). Thus, we termed this a super-activated macrophage state.  We observed the SLAMF7-induced super-activated macrophages across a range of diseases including rheumatoid arthritis, Crohn’s disease, and severe COVID-19 pneumonia. This implicates a central role for SLAMF7 in macrophage super-activation across many inflammatory diseases.

a) Simmons DP, Nguyen HN, Gomez-Rivas E, Jeong Y, Jonsson AH, Chen AF, Lange JK, Dyer GS, Blazar P, Earp BE, Coblyn JS, Massarotti EM, Sparks JA, Todd DJ; Accelerating Medicines Partnership (AMP) RA/SLE Network, Rao DA, Kim EY, Brenner MB.  SLAMF7 engagement superactivates macrophages in acute and chronic inflammation.  Sci. Immunol. 2022; 7:eabf2846.  PMCID: PMC8991457 

Pathologically expanded fibroblastic stromal cells in RA drive inflammation and tissue damage.

While fibroblastic stromal cells were known to play key roles in regulating immune responses in lymph nodes and tumors, our studies are defining their central roles in chronic inflammation in peripheral tissues.  Using RA as an example, we defined subsets of inflammatory synovial fibroblasts that are expanded in RA and account for over half of all fibroblasts in the disease. These are sublining fibroblasts that express high levels of HLA-DR, IL-6 and many chemokines, all expressed at even higher levels than leukocytes (Mizoguchi et al.  Nat. Comm. (2019), Fan et al. Nat. Immunol. (2019). Importantly, we noted that a particular inflammatory subpopulation of fibroblasts in the sublining was oriented around blood vessels.   We showed that blood vessel endothelial cell-derived Notch ligands drive Notch signaling on the fibroblasts which imparts their sublining phenotype and that this pathway is essential for inflammatory arthritis.  Either deletion or blockade of Notch 3 signaling abrogated inflammatory arthritis in mouse models (Wei et al. Nature (2020).  The figure (above) displays the perivascular (sublining) fibroblasts becoming activated by leukocyte-derived cytokines to become the major source of IL-6 and many chemokines and driving degradation of the cartilage, and bone erosion via osteoclast activation.

We then defined the inflammatory fibroblast populations that are shared across multiple tissues and diseases (including RA, IBD, lung ILD and Sjogren’s Disease) and found that the inflammatory and the Notch signaled fibroblasts are shared across tissues and diseases (Korsunsky et al Med 3: 481 (2022).

In identifying the pathways that activate stromal cell populations in autoimmune diseases, we defined signal specific gene expression modules in fibroblasts that regulate their secretion of IL-6 in chronically inflamed tissues. IL-6 is part of a larger 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 member, leukemia inhibitory factor receptor (LIFR). No matter what exogenous factors activate fibroblasts (e.g. TNF, IL-17, IL-1, LPS) the full activation response is dependent on autocrine induction of LIF which acts on the LIFR to profoundly amplify the activation response. Blocking the LIF-LIFR axis prevents fibroblast activation across a range of stimuli. We are now targeting autocrine amplification pathways in therapeutic approaches to block fibroblast-induced inflammation, fibrosis and tissue damage.

a) Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, Nguyen HN, Noss EH, Turner JD, Earp BE, Blazar PE, Wright J, Simmons BP, Donlin LT, Kalliolias GD, Goodman SM, Bykerk VP, Ivashkiv LB, Lederer JA, Hacohen N, Nigrovic PA, Filer A, Buckley CD, Raychaudhuri S, Brenner MB.  Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis.  Nat Commun.  2018; 9:789.  PMCID:  PMC5824882

b) Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, Croft AP, Watts J, Blazar PE, Lange JK, Thornhill TS, Filer A, Raza K, Donlin LT; Accelerating Medicines Partnership Rheumatoid Arthritis & Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Siebel CW, Buckley CD, Raychaudhuri S, Brenner MB.  Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 2020; 582:259-264. PMCID: PMC7841716

c) 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.  PMCID: PMC5567864

d) Zhang F*, Wei K*, Slowikowski K*, Fonseka CY, Rao DA*, … Donlin LT*, Anolik JH*, Brenner MB*,  Raychaudhuri S*. (* co-first, co-last authors) Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 2019; 20:928–942.  PMID: 31061532  PMCID: PMC6602051

Single cell disease deconstruction of RA:

I chaired the Accelerating Medicines Partnership (AMP) RA/SLE consortium for 6 years where we carried out extensive single cell disease deconstruction of RA synovial tissues.  We stratified RA patients based on the abundance of cell types in the synovial tissues.  Using deep single cell data, we defined receptors-ligand expression, expression of risk loci and using covarying neighbor analysis predicted the interacting cell types. I now co-lead the successor AMP AIM Consortium Technology Core that carries out the spatial transcriptomics and other single cell analysis across four diseases, RA, SLE, psoriasis and Sjogren’s Disease.  The trove of data generated allows us to continue elucidating the pathogenic interactions driving inflammation and tissue damage in these autoimmune diseases.

a) Zhang F*, Jonsson AH*, Nathan, A*, MillardN* ….. Wei K*, Rao DA*, Donlin LT*, Anolik, JH*, Brenner MB*, Raychaudhuri S* (* co-first, co-last authors) Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 2023; 623;616-624.

Earlier classical discoveries from the Brenner lab:

Discovery of  T cells and their functionals:

Discovery of the alpha beta T cell receptor (TCR) proteins and genes was one of the most important advances in immunology.  During that time, a third rearranging gene, initially thought to be TCR alpha, but later renamed TCR gamma, was identified.  It was initially thought to be a vestigial gene as all the rearrangements in alpha beta T cells were defective.  The Brenner lab revealed that an entirely separate lineage of T cells existed that expressed a TCR distinct from TCR alpha beta.  We found that one of the CD3-associated chains on these T cells was the functional protein product of the TCR gamma gene, and we found another protein associated in the complex that we named TCR delta.  We showed that gamma delta T cells were a separate population of mature effector T cells that lacked expression of functionally rearranged TCR alpha  or TCR beta genes.  We defined many of key functional characteristics of these cells including the fact that they did not recognize peptide-MHC presented antigens.  We were the first to propose and identify that their recognition focused on nonpeptide antigens, an idea that has now grown to be a common theme for all 3 groups of innate T cells (gamma delta T cells, CD1 restricted T cells (below) and MAIT cells).  Recently, we found that an invariant subpopulation of gamma delta T cells that produces IL-17 and expresses PLZF is highly enriched in adipose tissue where it critically regulates Treg cell numbers and adaptive thermogenesis.  Mice lacking these gamma delta T cells cannot maintain body temperature and die in the cold. Example publications below:

a) Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL, Seidman JG, Ip S, Rosen F, Krangel MS.  Identification of a putative second T-cell receptor.  Nature  1986; 322:145-149.

b) Brenner MB, McLean J, Scheft H, Riberdy J, Ang S-L, Seidman JG, Devlin P, Krangel MS.  Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes.  Nature 1987; 325:689-694.

c) Band H, Hochstenbach F, McLean J, Hata S, Krangel MS, Brenner MB.  Immunochemical proof that a novel rearranging gene encodes the T cell receptor delta subunit.  Science 1987; 238:682-684.

d) Kohlgruber AC, Gal-Oz S-T, LaMarche NM, Shimazaki M, Duquette D, Nguyen HN, Mina AI, Paras T, Tavakkoli A, von Andrian U, Banks AS, Shay T, Brenner MB* and Lynch L* (*authors contributed equally)  Gamma Delta T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis Nat. Immunol. 2018;19, 464-474. PMID: 29670241

Discovery of the pathway of lipid antigen presentation to T cells mediated by CD1 antigen-presenting molecules.

The paradigm for T cell recognition was based on the premise that MHC Class I and Class II antigen-presenting molecules present peptides for recognition by alpha beta TCRs.  Thus, it seemed almost impossible when we reported a series of papers in Nature (below) indicating that alpha beta (and gamma delta) T cells could recognize foreign antigens in the context of CD1 proteins (which are not encoded in the MHC). Even more remarkable was our finding that the antigens presented were lipids, not proteins. We defined many of the mechanisms that allow the CD1a, b, c and d proteins to intersect with and bind lipid antigens in endosomes. CD1a localizes to and surveys the early endocytic compartment, CD1b and d localize and survey late endosomes and lysosomes, while CD1c promiscuously surveys to bind lipid antigens throughout the endocytic system. We showed how saposins use different mechanisms to load lipids into CD1 proteins.  Together, these and related studies outlined the existence of an independent antigen-presentation system for T cells where the universe of lipid rather than peptide antigens are recognized by T cells.

In more recent studies on iNKT cells, we found that self-lipid antigens activate iNKT cells to upregulate FASL which signals IL-1 beta release from macrophages without inflammasome activation. This important 2-cell pathway enables IL-1 beta release from infected APCs when microbes can evade inflammasome activation (Donado et al. Cell Reports 2020; 31,107466).  Furter, we defined a regulatory population of iNKT cells that controls inflammation in adipose tissue by regulating adipose Tregs and M2/M1 macrophage homeostasis and regulates thermogenesis and obesity (Lynch et al 2015) and then found the remarkable ability of adipose iNKT cells to regulate fat burning, weight loss and thermogenesis (Lynch et al 2016). We have defined distinct subsets of iNKT cells in adipose tissue that 1) produce IL-10 as a result of an XBP1s ER stress pathway and 2) produce INFγ which activates NK cells to kill macrophages and control inflammation at steady state (LaMarche et al 2020).  Example publications below:

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

b) Moody DB, Young DC, Cheng T-Y, Rosat J-P, Roura-mir C, O’Connor PB, Zajonc DM, Walz A, Miller MJ, Levery SB, Wilson IA, Costello CE, Brenner MB.  T cell activation by lipopeptide antigens.  Science  2004; 303:527-531. 

c) van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng T-Y, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, and Brenner MB. Apolipoprotein-mediated pathways of lipid antigen presentation.  Nature 2005; 437:906-910. 

d) 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.  PMCID: PMC4343194

e) 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.   PMCID: PMC5061124

f) Donado CA, Cao AB, Simmons DP, Croker BA, Brennan PJ, Brenner MB.  A Two-Cell Model for IL-1 beta Release Mediated by Death-Receptor Signaling.  Cell Rep.  2020; 31:107466.  PMCID: PMC7192215

g) LaMarche NM, Kane H, Kohlgruber AC, Dong H, Lynch L, Brenner MB.  Distinct iNKT Cell Populations Use IFNγ or ER Stress-Induced IL-10 to Control Adipose Tissue Homeostasis.  Cell Metab. 2020; 32:243-258.  PMCID: PMC8234787

Current lab members:

Alisa Mueller, MD PhD (postdoctoral fellow):

Alisa is an Instructor in Medicine and Associate Physician at Brigham and Women’s Hospital and Harvard Medical School. She received her M.D. and Ph.D. degrees at Stanford University and completed her medicine residency and rheumatology fellowship at Brigham and Women’s Hospital. In the lab she has explored mechanisms driving stromal inflammation and pathogenicity in rheumatoid arthritis. Her work has identified non-canonical Wnt signaling as a

novel mechanism contributing to synovial fibroblast heterogeneity and inflammatory phenotype. In the figure, non-canonical Wnt pathway activation (blue line) increases the severity and duration of knee swelling in the antigen-induced arthritis mouse model of inflammatory arthritis. Experiments performed in collaboration with Adam Croft’s Laboratory. She has also led a research team to pioneer a CRISPR deletion screen and lentiviral overexpression screen to identify novel regulators of inflammatory fibroblasts.

Heather Faust PhD (postdoctoral fellow):

Heather received her PhD from Johns Hopkins School of Medicine in the Cellular and Molecular Medicine program. Her research focused on biomaterials-based approaches to treating osteoarthritis under the mentorship of Jennifer H. Elisseeff. During this time, she became interested in the role of immunology in arthritis and joined Michael's lab for post-doctoral studies. Here, she studies synovial fibroblasts and their pathologic alterations in arthritis. Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction (figure). Little is known about what regulates the homeostatic functions of fibroblasts. We found a gene expression program in healthy human synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identified cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11β1, resulted in loss of the healthy fibroblast phenotype in mouse synovium. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNFα- and TGFβ in vitro, while stimulation with these cytokines repressed cortisol signaling and adipogenesis. These findings support the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.

Erin Theisen, MD PhD (postdoctoral fellow):

Erin completed her MD/PhD training at the University of Wisconsin with John-Demian Sauer, where she studied the immunological consequences of Listeria monocytogenes activating the inflammasome. She then completed her dermatology residency at the Harvard Combined Dermatology Residency Program and continues to see patients with autoimmune skin diseases. In the Brenner lab, Erin is working on further defining the Granzyme K-complement pathway, particularly as it relates to skin diseases such as psoriasis and cutaneous lupus and is developing mouse models to define the in vivo consequences of the GzmK-complement pathway in both skin and arthritis models.

Granzyme K+ (GzmK) T-cells have been identified in numerous autoimmune diseases. GzmK, through direct cleavage of C2 and C4 can form an active C3 convertase on the surface of cells, where it can trigger the main downstream consequences of the complement cascade: opsonization, anaphylatoxin generation, and membrane attack complex formation. Use of GzmK -/- mice in various disease models, including imiquimod dermatitis as a model of psoriasis, and antigen-induced arthritis will further define the contributions of the GzmK-complement pathway to disease pathophysiology.

Hung Nguyen Ph.D. (postdoctoral fellow):

Hung received his PhD in Biology from the Massachusetts Institute of Technology. His postdoctoral work in the Brenner lab, working together with Erika Noss, Edy Kim, and Yunju Jeong, uncovered a key autocrine signaling pathway in pathogenic fibroblasts. This autocrine loop involving leukemia inhibitory factor (LIF) and LIF receptor acts as a master amplifier of fibroblast mediated inflammation and fibrosis.The autocrine LIF/LIFR acts as a second signal downstream of many pro-inflammatory and pro-fibrotic stimuli in fibroblasts. No matter what the upstream signal is, LIFR signaling is required to drive the pathogenic gene program. Thus, LIFR, a master amplifier of both inflammation and fibrosis, is a promising therapeutic target for chronic and inflammatory diseases, fibrotic disorders and cancer.

Shani T. Gal-Oz, Ph.D. (postdoctoral fellow):

Shani is a computational biologist, interested in autoimmune mechanisms sexual dimorphism in health and disease. She completed her PhD at the life sciences department in Ben Gurion University of the Negev in Israel, studying sexual dimorphism in the mice immune system in health and in response to interferon. As a postdoctoral fellow in the Brenner lab she is co-mentored by Dr. Ilya Korsunsky, and collaborates closely with Byung-Hee Ko to utilize single cell RNA sequencing and spatial transcriptomics data to study regulatory T cell sub populations in rheumatoid arthritis. In the figure, we identified 10 Treg sub-populations from three rheumatoid arthritis tissues: PBMCs, synovial fluid and synovial tissue; and PBMCs from healthy donors (control) are projected in UMAP embeddings. Two specific sub-populations of interest include CD25 high CXCR6+ Tregs (light orange) that are predominantly present in synovial fluid and synovial tissue, and AREG Tregs (green) that almost exclusively appear in the synovial tissue.

Carlos Donado Ph.D. (postdoctoral fellow):

Carlos obtained his PhD in Immunology at Harvard Medical School in 2021. During his graduate training in the Brenner laboratory, he identified an alternative pathway that triggers the release of interleukin-1 beta (IL-1 beta), a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. He found that a population of T cells with innate-like functions, invariant natural killer T cells, provide extracellular signals to infected phagocytes to trigger an alternative IL-1 beta release pathway that supersedes inflammasome activation during infection with inflammasome-evasive microbes. As a postdoctoral fellow in the Brenner lab, he has focused on elucidating the function of the population of CD8+ T cells defined by high expression of granzyme K, and which makes up the majority of tissue CD8+ T cells in inflamed organs across several inflammatory diseases. He discovered a new complement activation pathway that is entirely driven by granzyme K following its cleavage of the complement components C4 and C2 into C4b and C2b.  In the figure, GZMK-expressing CD8+ T cells constitutively release GZMK. Secreted GZMK can bind plasma membranes by interacting with heparan sulfate glycosaminoglycans, where it cleaves C4 and C2 generating C4b and C2b. Newly-cleaved C4b molecules can covalently bind membranes through their exposed thioester, associate with C2b, and form membrane-bound C3 convertases. These C3 convertases can cleave C3 into C3a and C3b. Nascent C3b molecules can opsonize target cells or associate with membrane-bound C3 convertases to form C5 convertases that can cleave C5 into C5a and C5b. C5b molecules associate with C6, C7, C8, and C9 to form a terminal complement complex (TCC).

Byung-Hee Koh, Ph.D. (postdoctoral fellow):

Byung-Hee received his Ph.D. at Indiana University School of Medicine in Dr. Mark Kaplan’s Lab, and currently work as a postdoctoral fellow in the Brenner Lab. His projects focus on determining the heterogeneity and functions of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA) in collaboration with Shani Gal-Oz. Using combined single cell RNA sequencing analysis and in vitro work, he defined functionally distinct Treg subsets: CXCR6+Tregs and Amphiregulin- expressing Tregs (AREG+Tregs).  CXCR6+ Tregs are derived through interaction with macrophages, and AREG+ Tregs are derived via interactions with fibroblasts. Our findings provide a comprehensive characterization of Treg heterogeneity in the RA joint and offer insights into the mechanisms that may control Treg maintenance and function in the context of chronic autoimmune inflammation.  In the figure (above), CXCR6+ Tregs have higher suppressive capability compared to other Treg subsets, while AREG+ Tregs induce IL-33-expressing RA-fibroblasts. Additionally, Tregs can also be converted to Tph cells, acquiring Tph cell function and phenotype while losing those of Tregs.

Ryota Sato, Ph.D. (postdoctoral fellow):

Ryota completed his Ph.D. at Yokohama City University in 2020. He is interested in how the immune system distinguishes self from non-self. His current studies focus on how self-tolerance is dysregulated in various autoimmune diseases, as represented by extraordinary phenotypes of regulatory T cells. He is defining the pathways that give rise to CD25 low Tregs which account for half of the Tregs in most autoimmune diseases and which are dysfunctional. In the figure, he shows CD25 expression on Treg cell in PBMC (peripheral blood mononuclear cell) derived from HD (healthy donor) or SLE (systemic lupus erythematosus) patients highlighting CD25 high and low populations.

Angela Zou (Graduate student, MD PhD program Harvard):

Angela is an MD/PhD student at Harvard Medical School interested in the basis of autoimmunity and inflammation. In the Brenner lab, she is studying the mechanisms governing pathological fibroblast activation in rheumatoid arthritis. Arid5b is a transcriptional co-regulator that associates with demethylases and deacetylaces to regulate gene expression.

In the figure, we show that fibroblasts can adopt both chronic inflammatory and tissue invasive functions in RA, yet how these behaviors are regulated is not known. We have found that the transcription factor Arid5b inhibits the inflammatory activation of fibroblasts while enhancing their invasiveness, providing insight into how pathologic fibroblast states are differentially programmed.

Suppawat (Kurt) Kongthong (Graduate student in Immunology at Harvard):

Kurt is a PhD student in the Immunology Program at Harvard Medical School. He uses genetic screens to identify and characterize novel regulators of inflammatory responses in primary fibroblasts. He grew up in Bangkok, Thailand, and received his BA in Biology from Columbia University in New York where he studied the roles of microbial metabolites in gut inflammatory responses with Dr. Nicholas Arpaia and developed methods to engineer and study gut microbes with Dr. Harris Wang.  He has now carried out a CRISPR screen in fibroblasts resulting in the identification of novel regulators of pathological fibroblast behavior.  In the figure, he shows a schematic of the CRISPR screen.

Gerald Watts (Senior Lab Manager):

Gerald has an MS degree in Biological Electron Microscopy from the University of Wales, Aberystwyth, and a BS in Biology with Microbiology from Imperial College, London. During his tenure in the Brenner Lab, his research has focused on CD1 lipid antigens in TB and fibroblast biology in rheumatoid arthritis, assisting researchers, past and present, in successfully bringing their projects to publication. A founding member and technical consultant of the BWH Center for Cellular Profiling core facility, the team provides single cell RNA sequencing and spatial transcriptomics expertise to the MGB community and beyond.

Madison Fairfield (Technician):

Madison graduated from Bowdoin College in 2023. She is interested in learning how the immune system works and the various ways to treat it when it malfunctions. She works with Erin Theisen and Heather Faust on a variety of projects involving GzmK, T cells and fibroblasts.