Photo of Mark A. Exley,  PhD

Mark A. Exley, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital


mexley@partners.org

Mark A. Exley, PhD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

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Our primary research interests are in regulation of the immune system by CD1d-reactive NKT cells and how to utilize this knowledge clinically in cancer and other diseases. CD1d is expressed on myeloid cells, lymphocytes, heart, liver, and in the gut. Bi-directional interactions between CD1d+ cells and CD1d-reactive NKT profoundly influence immune responses. Our recent contributions include establishing a physiological role for CD1d-reactive NKT and defining the human populations of these cells in health and disease. Advanced cancer patients have few and anti-inflammatory polarized CD1d-reactive NKT, which may suppress their anti-tumor activity. Bone marrow CD1d-reactive T cells have a profound anti-inflammatory bias with potential to suppress graft-versus-host disease. Conversely, HCV+ human liver also contains large numbers of CD1d-reactive NKT, but with a pro-inflammatory bias, which may contribute to both protective and pathogenic responses in hepatitis and hepatocellular carcinoma. These results support a role for these cells in immune decision making with potential therapeutic applications. We are supporting clinical trials to exploit NKT cells in cancer and other diseases. We are also following up identification of a physiological role for CD1d-reactive NKT in resistance to viral infections through activation of NK and conventional T cells. Finally, we have identified a protective role of NKT cells in obesity and consequent metabolic syndrome.

Publications

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  • Zeng SG, Ghnewa YG, O'Reilly VP, Lyons VG, Atzberger A, Hogan AE, Exley MA, Doherty DG. Human invariant NKT cell subsets differentially promote differentiation, antibody production, and T cell stimulation by B cells in vitro. J Immunol 2013; 191:1666-76. PubMed
  • Mangan BA, Dunne MR, O'Reilly VP, Dunne PJ, Exley MA, O'Shea D, Scotet E, Hogan AE, Doherty DG. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human V隆3 T cells. J Immunol 2013; 191:30-4. PubMed
  • Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O'Shea D, O'Farrelly C, Exley MA. Adipose Tissue Invariant NKT Cells Protect against Diet-Induced Obesity and Metabolic Disorder through Regulatory Cytokine Production. Immunity 2012; 37:574-87. PubMed
  • Li S, Vriend LE, Nasser IA, Popov Y, Afdhal NH, Koziel MJ, Schuppan D, Exley MA, Alatrakchi N. Hepatitis C virus-specific T cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology 2012. PubMed
  • Exley MA. Editorial: NKT get the 'flu: NKT cells as (mostly) good guys in influenza; monocytic cells as double agents. J Leukoc Biol 2012; 91:349-52. PubMed
  • Exley MA, Lynch L, Varghese B, Nowak M, Alatrakchi N, Balk SP. Developing understanding of the roles of CD1d-restricted T cell subsets in cancer: reversing tumor-induced defects. Clin Immunol 2011; 140:184-95. PubMed
  • Exley MA, Nakayama T. NKT-cell-based immunotherapies in clinical trials. Clin Immunol 2011; 140:117-8. PubMed
  • Zeissig S, Dougan SK, Barral DC, Junker Y, Chen Z, Kaser A, Ho M, Mandel H, McIntyre A, Kennedy SM, Painter GF, Veerapen N, Besra GS, Cerundolo V, Yue S, Beladi S, Behar SM, Chen X, Gumperz JE, Breckpot K, Raper A, Baer A, Exley MA, Hegele RA, Cuchel M, Rader DJ, Davidson NO, Blumberg RS. Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. J Clin Invest 2010; 120:2889-99. PubMed
  • Exley MA, Wilson B, Balk SP. Isolation and functional use of human NKT cells. Curr Protoc Immunol 2010; Chapter 14:Unit 14.11. PubMed
  • Nowak M, Lynch L, Yue S, Ohta A, Sitkovsky M, Balk SP, Exley MA. The A2aR adenosine receptor controls cytokine production in iNKT cells. Eur J Immunol 2010; 40:682-7. PubMed
  • Yue SC, Nowak M, Shaulov-Kask A, Wang R, Yue D, Balk SP, Exley MA. Direct CD1d-mediated stimulation of APC IL-12 production and protective immune response to virus infection in vivo. J Immunol 2009; 184:268-76. PubMed
  • Nowak M, Arredouani MS, Tun-Kyi A, Schmidt-Wolf I, Sanda MG, Balk SP, Exley MA. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with alpha-galactosylceramide. PLoS ONE 2010; 5:e11311. PubMed
  • Teng MW, Sharkey J, McLaughlin NM, Exley MA, Smyth MJ. CD1d-based combination therapy eradicates established tumors in mice. J Immunol 2009; 183:1911-20. PubMed
  • Teng MW,Yue S,Sharkey J,Exley MA,Smyth MJ. CD1d activation and blockade: a new antitumor strategy. J Immunol 2009; 182:3366-71. PubMed
  • Song W,van der Vliet HJ,Tai YT,Prabhala R,Wang R,Podar K,Catley L,Shammas MA,Anderson KC,Balk SP,Exley MA,Munshi NC. Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin Cancer Res 2008; 14:6955-62. PubMed
  • van der Vliet HJ,Wang R,Yue SC,Koon HB,Balk SP,Exley MA. Circulating myeloid dendritic cells of advanced cancer patients result in reduced activation and a biased cytokine profile in invariant NKT cells. J Immunol 2008; 180:7287-93. PubMed
  • Exley MA,Hou R,Shaulov A,Tonti E,Dellabona P,Casorati G,Akbari O,Akman HO,Greenfield EA,Gumperz JE,Boyson JE,Balk SP,Wilson SB. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. Eur J Immunol 2008; 38:1756-66. PubMed
  • Shaulov A, Yue S, Wang R, Joyce RM, Balk SP, Kim HT, Avigan DE, Uhl L, Sackstein R, Exley MA. Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: Implications for posttransplant survival. Exp Hematol 2008; 36:464-72. PubMed
  • van der Vliet HJ, Koon HB, Atkins MB, Balk SP, Exley MA. Exploiting regulatory T-cell populations for the immunotherapy of cancer. J Immunother 2007; 30:591-5. PubMed
  • Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ. Hepatitis C Virus (HCV)-Specific CD8+ Cells Produce Transforming Growth Factor {beta} That Can Suppress HCV-Specific T-Cell Responses. J Virol 2007; 81:5882-92. PubMed
  • Speak AO, Salio M, Neville DC, Fontaine J, Priestman DA, Platt N, Heare T, Butters TD, Dwek RA, Trottein F, Exley MA, Cerundolo V, Platt FM. Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals. Proc Natl Acad Sci U S A 2007; 104:5971-6. PubMed
  • van Dervliet HJ, Koon HB, Yue SC, Uzunparmak B, Seery V, Gavin MA, Rudensky AY, Atkins MB, Balk SP, Exley MA. Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer. Clin Cancer Res 2007; 13:2100-8. PubMed
  • Yanagisawa K, Exley MA, Jiang X, Ohkochi N, Taniguchi M, Seino K. Hyporesponsiveness to natural killer T-cell ligand alpha-galactosylceramide in cancer-bearing state mediated by CD11b+ Gr-1+ cells producing nitric oxide. Cancer Res 2006; 66:11441-6. PubMed
  • van der Vliet HJ, Balk SP, Exley MA. Natural killer T cell-based cancer immunotherapy. Clin Cancer Res 2006; 12:5921-3. PubMed
  • Lang GA, Exley MA, Lang ML. The CD1d-binding glycolipid alpha-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology 2006; 119:116-25. PubMed
  • Ilyinskii PO, Wang R, Balk SP, Exley MA. CD1d mediates T-cell-dependent resistance to secondary infection with encephalomyocarditis virus (EMCV) in vitro and immune response to EMCV infection in vivo. J Virol 2006; 80:7146-58. PubMed
  • Boyson JE, Nagarkatti N, Nizam L, Exley MA, Strominger JL. Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss. Proc Natl Acad Sci U S A 2006; 103:4580-5. PubMed
  • Sonoda KH, Sakamoto T, Qiao H, Hisatomi T, Oshima T, Tsutsumi-Miyahara C, Exley M, Balk SP, Taniguchi M, Ishibashi T. The analysis of systemic tolerance elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated immune deviation. Immunology 2005; 116:390-9. PubMed
  • Yue SC, Shaulov A, Wang R, Balk SP, Exley MA. CD1d ligation on human monocytes directly signals rapid NF-kappaB activation and production of bioactive IL-12. Proc Natl Acad Sci U S A 2005; 102:11811-6. PubMed
  • Dougan SK, Salas A, Rava P, Agyemang A, Kaser A, Morrison J, Khurana A, Kronenberg M, Johnson C, Exley M, Hussain MM, Blumberg RS. Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells. J Exp Med 2005; 202:529-39. PubMed
  • Cho S, Knox KS, Kohli LM, He JJ, Exley MA, Wilson SB, Brutkiewicz RR. Impaired cell surface expression of human CD1d by the formation of an HIV-1 Nef/CD1d complex. Virology 2005; 337:242-52. PubMed
  • Nieuwenhuis EE, Gillessen S, Scheper RJ, Exley MA, Taniguchi M, Balk SP, Strominger JL, Dranoff G, Blumberg RS, Wilson SB. CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 2005; 14:250-8. PubMed
  • Exley MA, Koziel MJ. To be or not to be NKT: natural killer T cells in the liver. Hepatology 2004; 40:1033-40. PubMed
  • Durante-Mangoni E, Wang R, Shaulov A, He Q, Nasser I, Afdhal N, Koziel MJ, Exley MA. Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells. J Immunol 2004; 173:2159-66. PubMed
  • Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004; 113:1490-7. PubMed
  • Exley MA, Bigley NJ, Cheng O, Shaulov A, Tahir SM, Carter QL, Garcia J, Wang C, Patten K, Stills HF, Alt FW, Snapper SB, Balk SP. Innate immune response to encephalomyocarditis virus infection mediated by CD1d. Immunology 2003; 110:519-26. PubMed
  • Levy O, Orange JS, Hibberd P, Steinberg S, LaRussa P, Weinberg A, Wilson SB, Shaulov A, Fleisher G, Geha RS, Bonilla FA, Exley M. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis 2003; 188:948-53. PubMed
  • Gansuvd B, Hubbard WJ, Hutchings A, Thomas FT, Goodwin J, Wilson SB, Exley MA, Thomas JM. Phenotypic and functional characterization of long-term cultured rhesus macaque spleen-derived NKT cells. J Immunol 2003; 171:2904-11. PubMed
  • Gillessen S, Naumov YN, Nieuwenhuis EE, Exley MA, Lee FS, Mach N, Luster AD, Blumberg RS, Taniguchi M, Balk SP, Strominger JL, Dranoff G, Wilson SB. CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion. Proc Natl Acad Sci U S A 2003; 100:8874-9. PubMed
  • Huber S, Sartini D, Exley M. Role of CD1d in coxsackievirus B3-induced myocarditis. J Immunol 2003; 170:3147-53. PubMed
  • Huber SA, Sartini D, Exley M. Vgamma4(+) T cells promote autoimmune CD8(+) cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4(+) Th1 cells. J Virol 2002; 76:10785-90. PubMed
  • Boyson JE, Rybalov B, Koopman LA, Exley M, Balk SP, Racke FK, Schatz F, Masch R, Wilson SB, Strominger JL. CD1d and invariant NKT cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 2002; 99:13741-6. PubMed
  • Nieuwenhuis EE, Matsumoto T, Exley M, Schleipman RA, Glickman J, Bailey DT, Corazza N, Colgan SP, Onderdonk AB, Blumberg RS. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat Med 2002; 8:588-93. PubMed
  • Exley MA, He Q, Cheng O, Wang RJ, Cheney CP, Balk SP, Koziel MJ. Cutting edge: Compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver. J Immunol 2002; 168:1519-23. PubMed
  • Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, Porcelli S, Maclaren N. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002; 109:131-40. PubMed
  • Exley MA, Tahir SM, Cheng O, Shaulov A, Joyce R, Avigan D, Sackstein R, Balk SP. A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J Immunol 2001; 167:5531-4. PubMed
  • Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, Balk SP, Exley MA. Loss of IFN-gamma production by invariant NK T cells in advanced cancer. J Immunol 2001; 167:4046-50. PubMed
  • Stremmel C, Exley M, Balk S, Hohenberger W, Kuchroo VK. Characterization of the phenotype and function of CD8(+), alpha / beta(+) NKT cells from tumor-bearing mice that show a natural killer cell activity and lyse multiple tumor targets. Eur J Immunol 2001; 31:2818-28. PubMed
  • Exley MA, Bigley NJ, Cheng O, Tahir SM, Smiley ST, Carter QL, Stills HF, Grusby MJ, Koezuka Y, Taniguchi M, Balk SP. CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus. J Leukoc Biol 2001; 69:713-8. PubMed
  • Wang B, Chun T, Rulifson IC, Exley M, Balk SP, Wang CR. Human CD1d functions as a transplantation antigen and a restriction element in mice. J Immunol 2001; 166:3829-36. PubMed
  • Dao T, Exley M, Mehal WZ, Tahir SM, Snapper S, Taniguchi M, Balk SP, Crispe IN. Involvement of CD1 in peripheral deletion of T lymphocytes is independent of NK T cells. J Immunol 2001; 166:3090-7. PubMed
  • Saubermann LJ, Beck P, De Jong YP, Pitman RS, Ryan MS, Kim HS, Exley M, Snapper S, Balk SP, Hagen SJ, Kanauchi O, Motoki K, Sakai T, Terhorst C, Koezuka Y, Podolsky DK, Blumberg RS. Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice. Gastroenterology 2000; 119:119-28. PubMed
  • Exley M, Garcia J, Wilson SB, Spada F, Gerdes D, Tahir SM, Patton KT, Blumberg RS, Porcelli S, Chott A, Balk SP. CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes. Immunology 2000; 100:37-47. PubMed
  • Sonoda KH, Exley M, Snapper S, Balk SP, Stein-Streilein J. CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site. J Exp Med 1999; 190:1215-26. PubMed
  • Kim HS, Garcia J, Exley M, Johnson KW, Balk SP, Blumberg RS. Biochemical characterization of CD1d expression in the absence of beta2-microglobulin. J Biol Chem 1999; 274:9289-95. PubMed
  • Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA. Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. Nature 1998; 391:177-81. PubMed
  • Exley M, Garcia J, Balk SP, Porcelli S. Requirements for CD1d recognition by human invariant Valpha24+ CD4-CD8- T cells. J Exp Med 1997; 186:109-20. PubMed
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