Michael G. Brown

Education

  • BS, Virginia Tech University
  • PhD, Medical College of Virginia, Virginia Commonwealth University
  • Postdoc, Mount Sinai School of Medicine
  • Postdoc, Washington University

Primary Appointment

  • Professor of Medicine, Medicine- Nephrology

Contact

Research Interest(s)

Natural Killer Cells, Viral Immunity, Genetic basis of host resistance to viral infection, Tumor immunity, Immune cell regulation

Research Description

A main goal of research in the Brown Lab centers on the genetics of host resistance to viral infection, and the role of natural killer (NK) cells in viral immunity. We aim to understand (1) how genetic variation shapes both innate and adaptive immune cell features, and how these differences further affect immune cells needed to detect and clear viral pathogens; (2) how NK cell effector function is acquired and regulated by both genetic and environmental influences; and (3) how NK responses to immune stimulation can specifically regulate adaptive immune outcomes.

We have learned that the major histocompatibility complex (MHC) exerts substantial control over NK cells, and we have developed several informative mouse models to explore this effect in much greater depth. We found that MHC class I-dependent education (also referred to as licensing), affects the capacity of NK cells to mediate virus-specific clearance, in addition to its effect on NK cell functionality. We hypothesize that licensing impacts NK-mediated responsiveness to cancer cells, as well. While the molecular basis of licensing remains poorly defined, the model systems and resources now developed in the lab provide an outstanding way to explore the basis and vital roles of NK cells in viral or tumor immunity.

Selected Publications

  • Brown M, Gamache A, Nash W, Cronk J. Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem. Journal of leukocyte biology. 2018. PMID: 30500089
  • Shi L, Li K, Guo Y, Banerjee A, Wang Q, Lorenz U, Parlak M, Sullivan L, Onyema O, Arefanian S, Stelow E, Brautigan D, Bullock T, Brown M, Krupnick A. Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(46): 11808-11813. PMID: 30381460 | PMCID: PMC6243255
  • Gillespie A, Lee H, Robertson C, Cabot M, Brown M. Genome-Wide Exome Analysis of Cmv5-Disparate Mouse Strains that Differ in Host Resistance to Murine Cytomegalovirus Infection. G3 (Bethesda, Md.). 2017;7(6): 1979-1984. PMID: 28450376 | PMCID: PMC5473773
  • Nash W, Gillespie A, Brown M. Murine Cytomegalovirus Disrupts Splenic Dendritic Cell Subsets via Type I Interferon-Dependent and -Independent Mechanisms. Frontiers in immunology. 2017;8 251. PMID: 28337202 | PMCID: PMC5343017
  • Gillespie A, Teoh J, Lee H, Prince J, Stadnisky M, Anderson M, Nash W, Rival C, Wei H, Gamache A, Farber C, Tung K, Brown M. Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection. PLoS pathogens. 2016;12(2): e1005419. PMID: 26845690 | PMCID: PMC4742223
  • Krueger P, Narayanan S, Surette F, Brown M, Sung S, Hahn Y. Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells. Journal of leukocyte biology. 2016;101(1): 329-338. PMID: 27493244
  • Teoh J, Gamache A, Gillespie A, Stadnisky M, Yagita H, Bullock T, Brown M. Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation. Journal of immunology (Baltimore, Md. : 1950). 2016;197(11): 4360-4370. PMID: 27798162 | PMCID: PMC5123769
  • Brown M, Erickson L. Editorial: NK cell reaping of Tfh cells: reckless slaughter or sensible pruning? Journal of leukocyte biology. 2015;98(2): 139-42. PMID: 26048981
  • Nash W, Teoh J, Wei H, Gamache A, Brown M. Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control. Frontiers in immunology. 2014;5 175. PMID: 24795719 | PMCID: PMC3997006
  • Wei H, Nash W, Makrigiannis A, Brown M. Impaired NK-cell education diminishes resistance to murine CMV infection. European journal of immunology. 2014. PMID: 25187217 | PMCID: PMC4233007
  • Prince J, Lundgren A, Stadnisky M, Nash W, Beeber A, Turner S, Brown M. Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control. Journal of immunology (Baltimore, Md. : 1950). 2013;191(9): 4709-19. PMID: 24068668 | PMCID: PMC3820117
  • Ge Y, Brown M, Wang H, Fu S. Genetic approach to study lupus glomerulonephritis. Methods in molecular biology (Clifton, N.J.). 2012;900 271-90. PMID: 22933074 | PMCID: PMC3873643
  • Lundgren A, Kim S, Stadnisky M, Brown M. Rapid discrimination of MHC class I and killer cell lectin-like receptor allele variants by high-resolution melt analysis. Immunogenetics. 2012;64(8): 633-40. PMID: 22752191 | PMCID: PMC3596047
  • Carroll V, Lundgren A, Wei H, Sainz S, Tung K, Brown M. Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease. Journal of virology. 2011;86(4): 2132-42. PMID: 22156514 | PMCID: PMC3302420
  • Stadnisky M, Xie X, Coats E, Bullock T, Brown M. Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. Blood. 2011;117(19): 5133-41. PMID: 21436069 | PMCID: PMC3109538
  • Lassen M, Lukens J, Dolina J, Brown M, Hahn Y. Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. Journal of immunology (Baltimore, Md. : 1950). 2010;184(5): 2693-701. PMID: 20124099 | PMCID: PMC2885840
  • Xie X, Stadnisky M, Coats E, Ahmed Rahim M, Lundgren A, Xu W, Makrigiannis A, Brown M. MHC class I D(k) expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(19): 8754-9. PMID: 20421478 | PMCID: PMC2889336
  • Rodriguez M, Lundgren A, Sabastian P, Li Q, Churchill G, Brown M. A Cmv2 QTL on chromosome X affects MCMV resistance in New Zealand male mice. Mammalian genome : official journal of the International Mammalian Genome Society. 2009;20(7): 414-23. PMID: 19641964 | PMCID: PMC2767104
  • Stadnisky M, Manichaikul A, Lundgren A, Brown M. NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection. Immunogenetics. 2009;61(11): 755-64. PMID: 19820922 | PMCID: PMC2880465
  • Xie X, Stadnisky M, Brown M. MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus. Journal of immunology (Baltimore, Md. : 1950). 2009;182(11): 7163-71. PMID: 19454713 | PMCID: PMC2730597
  • Brown M, Scalzo A. NK gene complex dynamics and selection for NK cell receptors. Seminars in immunology. 2008;20(6): 361-8. PMID: 18640056 | PMCID: PMC2646111
  • Li L, Huang L, Sung S, Lobo P, Brown M, Gregg R, Engelhard V, Okusa M. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. Journal of immunology (Baltimore, Md. : 1950). 2007;178(9): 5899-911. PMID: 17442974
  • Xie X, Dighe A, Clark P, Sabastian P, Buss S, Brown M. Deficient major histocompatibility complex-linked innate murine cytomegalovirus immunity in MA/My.L-H2b mice and viral downregulation of H-2k class I proteins. Journal of virology. 2006;81(1): 229-36. PMID: 17050600 | PMCID: PMC1797260
  • Dighe A, Rodriguez M, Sabastian P, Xie X, McVoy M, Brown M. Requisite H2k role in NK cell-mediated resistance in acute murine cytomegalovirus-infected MA/My mice. Journal of immunology (Baltimore, Md. : 1950). 2005;175(10): 6820-8. PMID: 16272339
  • Scalzo A, Manzur M, Forbes C, Brown M, Shellam G. NK gene complex haplotype variability and host resistance alleles to murine cytomegalovirus in wild mouse populations. Immunology and cell biology. 2005;83(2): 144-9. PMID: 15748210
  • Rodriguez M, Sabastian P, Clark P, Brown M. Cmv1-independent antiviral role of NK cells revealed in murine cytomegalovirus-infected New Zealand White mice. Journal of immunology (Baltimore, Md. : 1950). 2004;173(10): 6312-8. PMID: 15528370
  • Scalzo A, Wheat R, Dubbelde C, Stone L, Clark P, Du Y, Dong N, Stoll J, Yokoyama W, Brown M. Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus. Immunogenetics. 2003;55(6): 370-8. PMID: 12920489
  • Wheat R, Clark P, Brown M. Quantitative measurement of infectious murine cytomegalovirus genomes in real-time PCR. Journal of virological methods. 2003;112(1): 107-13. PMID: 12951218
  • Brown M, Dokun A, Heusel J, Smith H, Beckman D, Blattenberger E, Dubbelde C, Stone L, Scalzo A, Yokoyama W. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science (New York, N.Y.). 2001;292(5518): 934-7. PMID: 11340207
  • Brown M, Scalzo A, Stone L, Clark P, Du Y, Palanca B, Yokoyama W. Natural killer gene complex (Nkc) allelic variability in inbred mice: evidence for Nkc haplotypes. Immunogenetics. 2001;53(7): 584-91. PMID: 11685471
  • Brown M, Zhang J, Du Y, Stoll J, Yokoyama W, Scalzo A. Localization on a physical map of the NKC-linked Cmv1 locus between Ly49b and the Prp gene cluster on mouse chromosome 6. Journal of immunology (Baltimore, Md. : 1950). 1999;163(4): 1991-9. PMID: 10438936
  • Scalzo A, Brown M, Chu D, Heusel J, Yokoyama W, Forbes C. Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci. Immunogenetics. 1999;49(3): 238-41. PMID: 9914339
  • Ho E, Heusel J, Brown M, Matsumoto K, Scalzo A, Yokoyama W. Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(11): 6320-5. PMID: 9600963 | PMCID: PMC27675
  • Brown M, Fulmek S, Matsumoto K, Cho R, Lyons P, Levy E, Scalzo A, Yokoyama W. A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6. Genomics. 1997;42(1): 16-25. PMID: 9177771
  • Brown M, Scalzo A, Matsumoto K, Yokoyama W. The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity. Immunological reviews. 1997;155 53-65. PMID: 9059882
  • Forbes C, Brown M, Cho R, Shellam G, Yokoyama W, Scalzo A. The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6. Genomics. 1997;41(3): 406-13. PMID: 9169139
  • Yokoyama W, Matsumoto K, Scalzo A, Brown M. Molecular genetics of the natural killer gene complex and innate immunity. Biochemical Society transactions. 1997;25(2): 691-5. PMID: 9191184
  • Brown M, Driscoll J, Monaco J. MHC-linked low-molecular mass polypeptide subunits define distinct subsets of proteasomes. Implications for divergent function among distinct proteasome subsets. Journal of immunology (Baltimore, Md. : 1950). 1993;151(3): 1193-204. PMID: 8335924
  • Driscoll J, Brown M, Finley D, Monaco J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature. 1993;365(6443): 262-4. PMID: 8371781
  • Brown M, Driscoll J, Monaco J. Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. Nature. 1991;353(6342): 355-7. PMID: 1922341
  • Cho S, Attaya M, Brown M, Monaco J. A cluster of transcribed sequences between the Pb and Ob genes of the murine major histocompatibility complex. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(12): 5197-201. PMID: 1711220 | PMCID: PMC51839