- Biomedical Sciences Graduate Program | Michael G. Brown

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, Medicine- Nephrology

Contact

Research Interest(s)

NK Cells and Viral Immunity, Genetics of host resistance to viral infection, Immunogenetics, Immune regulation

Research Description

Immunology, Molecular Biology and Genetics

Natural killer (NK) cells are essential lymphocytes needed to arm the innate immune defense system. They mediate lysis of virus-infected and malignant target cells. As a result, NK cells supply vital protection that helps to prevent the spread of viral infection, or the development and progression of cancer. Viral pathogens and cancer cells, however, try to evade NK cell defenses using many different strategies. Ongoing research studies in the laboratory center on the role of NK cells in innate viral immunity. We also explore how viral pathogens and tumor cells try to escape NK-mediated immune control. Classical genetics approaches have been used to identify and characterize key genetic factors that control major NK cell features, including NK responsiveness to stimulation, NK lysis of virus-infected and tumor target cells, and NK-mediated resistance to viral infection. As central mediators of immunity, NK cells also regulate other immune cells, including dendritic cells and T cells. Recent studies have shown that NK cells can either negatively or positively affect virus-specific T cell effectors during viral infection. Additional studies in the laboratory therefore focus on the regulatory role of NK cells during priming and differentiation of virus-specific effector T cells, and the development of protective immune memory.

Selected Publications

  • 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