Cornelis P. Terhorst, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-7147
Fax: (617) 667-7140


terhorst@caregroup.harvard.edu

Cornelis P. Terhorst, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Chief, Immunology, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

1. Assembly and signal transduction of the T cell receptor for antigen.

To examine the role of the CD3 genes in thymocyte development and in T cell function we study mice in which the CD3 genes have been eliminated by homologous recombination techniques. Interestingly, overexpression of CD3epsilon initiates T lymphomagenesis at a very high frequency in transgenic mice made with different constructs.

2. Influence of the co-stimulators SLAM and CD38 on TCR and BCR cell signal transduction.

SLAM and CD38 initiated signal transduction in T and B cells utilizes novel mechanisms not shared by any of the other co-receptors

3. X-linked lymphoproliferative disease (XLP) is a rare disease in which young boys frequently die of fatal infectious mononucleosis and EBV induced lymphomas. We have recently cloned the gene for XLP and found that it binds to a specific site of the cytoplasmic tail of SLAM, a glycoprotein that is expressed on the surface of activated B and T cells. SAP, comprising an SH2-domain and a very short tail acts as an inhibitor molecule by blocking recruitment of other SH2-domain containing signal transduction molecules to a docking site in the SLAMcytoplasmic domain. Mice with a targeted disruption in the SAP or the SLAM gene have been generated. These permit a further dissection of the role of these genes in the immune defense against viruses.

4. Animal models of Inflammatory Bowel Disease.

Three models for experimental enterocolitis are used in the Terhorst lab, one is based on bone marrow transplantation, a second uses adoptive transfers of T cell subsets and a third uses the mutations bred into the IL-2null mouse which develops spontaneous chronic colitis.

5. Interplay between NK cells and T lymphocytes.

Mice that are deficient in NK cells are used to study innate immune responses to viruses and parasites.

Publications

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  • Biswas M, Sarkar D, Kumar SR, Nayak S, Rogers GL, Markusic DM, Liao G, Terhorst C, Herzog RW. Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg. Blood 2015. PubMed
  • Wang X, Su J, Sherman A, Rogers GL, Liao G, Hoffman BE, Leong KW, Terhorst C, Daniell H, Herzog RW. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells. Blood 2015. PubMed
  • O'Keeffe MS, Song JH, Liao G, De Calisto J, Halibozek PJ, Mora JR, Bhan AK, Wang N, Reinecker HC, Terhorst C. SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8(+) T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 2015. PubMed
  • Liao G, O'Keeffe MS, Wang G, van Driel B, de Waal Malefyt R, Reinecker HC, Herzog RW, Terhorst C. Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells. 2014; 5:35. PubMed
  • De Calisto J, Wang N, Wang G, Yigit B, Engel P, Terhorst C. SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors. 2014; 5:186. PubMed
  • Deng GM, Beltran J, Chen C, Terhorst C, Tsokos GC. T cell CD3龍 deficiency enables multiorgan tissue inflammation. J Immunol 2013; 191:3563-7. PubMed
  • Detre C, Yigit B, Keszei M, Castro W, Magelky EM, Terhorst C. SAP modulates B cell functions in a genetic background-dependent manner. Immunol Lett 2013; 153:15-21. PubMed
  • Martino AT, Basner-Tschakarjan E, Markusic DM, Finn JD, Hinderer C, Zhou S, Ostrov DA, Srivastava A, Ertl HC, Terhorst C, High KA, Mingozzi F, Herzog RW. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 2013; 121:2224-33. PubMed
  • Chatterjee M, Hedrich CM, Rauen T, Ioannidis C, Terhorst C, Tsokos GC. CD3-T Cell Receptor Co-stimulation through SLAMF3 and SLAMF6 Receptors Enhances ROR粒t Recruitment to the IL17A Promoter in Human T Lymphocytes. J Biol Chem 2012; 287:38168-77. PubMed
  • Wang X, Sherman A, Liao G, Leong KW, Daniell H, Terhorst C, Herzog RW. Mechanism of oral tolerance induction to therapeutic proteins. Adv Drug Deliv Rev 2012. PubMed
  • Detre C, Keszei M, Garrido-Mesa N, Kis-Toth K, Castro W, Agyemang AF, Veerapen N, Besra GS, Carroll MC, Tsokos GC, Wang N, Leadbetter EA, Terhorst C. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses. Blood 2012; 120:122-9. PubMed
  • Hoffman BE, Martino AT, Sack BK, Cao O, Liao G, Terhorst C, Herzog RW. Nonredundant Roles of IL-10 and TGF-硫 in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer. Mol Ther 2011. PubMed
  • Keszei M, Latchman YE, Vanguri VK, Brown DR, Detre C, Morra M, Arancibia CV, Paul E, Calpe S, Castro W, Wang N, Terhorst C, Sharpe AH. Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice. Int Immunol 2011; 23:149-58. PubMed
  • Wang N, Calpe S, Westcott J, Castro W, Ma C, Engel P, Schatzle JD, Terhorst C. Cutting Edge: The Adapters EAT-2A and -2B Are Positive Regulators of CD244- and CD84-Dependent NK Cell Functions in the C57BL/6 Mouse. J Immunol 2010; 185:5683-7. PubMed
  • Sintes J, Romero X, de Salort J, Terhorst C, Engel P. Mouse CD84 is a pan-leukocyte cell-surface molecule that modulates LPS-induced cytokine secretion by macrophages. J Leukoc Biol 2010; 88:687-97. PubMed
  • Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med 2010; 207:1541-54. PubMed
  • Detre C, Keszei M, Romero X, Tsokos GC, Terhorst C. SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions. Semin Immunopathol 2010; 32:157-71. PubMed
  • Porcelli S, Brenner MB, Greenstein JL, Terhorst C, Balk SP, Bleicher PA. Pillars Article: Recognition of Cluster of Differentiation 1 Antigens by Human CD4-CD8- CytolyticT Lymphocyte. Nature. 1989. 341: 447-450. J Immunol 2010; 184:3306-9. PubMed
  • Liao G, Nayak S, Regueiro JR, Berger SB, Detre C, Romero X, de Waal Malefyt R, Chatila TA, Herzog RW, Terhorst C. GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells. Int Immunol 2010; 22:259-70. PubMed
  • Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley KM, Detre C, Keszei M, Walter JE, Feldman L, Cheng HL, Poliani PL, Wang JH, Balter BB, Recher M, Andersson EM, Zha S, Giliani S, Terhorst C, Alt FW, Yan CT. Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. Proc Natl Acad Sci U S A 2010; 107:3024-9. PubMed
  • Cooper M, Nayak S, Hoffman BE, Terhorst C, Cao O, Herzog RW. Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer. Hum Gene Ther 2009; 20:767-76. PubMed
  • Martino AT, Nayak S, Hoffman BE, Cooper M, Liao G, Markusic DM, Byrne BJ, Terhorst C, Herzog RW. Tolerance induction to cytoplasmic beta-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity. PLoS ONE 2009; 4:e6376. PubMed
  • Morra M, Barrington RA, Abadia-Molina AC, Okamoto S, Julien A, Gullo C, Kalsy A, Edwards MJ, Chen G, Spolski R, Leonard WJ, Huber BT, Borrow P, Biron CA, Satoskar AR, Carroll MC, Terhorst C. Defective B cell responses in the absence of SH2D1A. Proc Natl Acad Sci U S A 2005; 102:4819-23. PubMed
  • Chung B, Aoukaty A, Dutz J, Terhorst C, Tan R. Signaling lymphocytic activation molecule-associated protein controls NKT cell functions. J Immunol 2005; 174:3153-7. PubMed
  • Schmidt-Supprian M, Tian J, Ji H, Terhorst C, Bhan AK, Grant EP, Pasparakis M, Casola S, Coyle AJ, Rajewsky K. I kappa B kinase 2 deficiency in T cells leads to defects in priming, B cell help, germinal center reactions, and homeostatic expansion. J Immunol 2004; 173:1612-9. PubMed
  • Wang N, Satoskar A, Faubion W, Howie D, Okamoto S, Feske S, Gullo C, Clarke K, Sosa MR, Sharpe AH, Terhorst C. The cell surface receptor SLAM controls T cell and macrophage functions. J Exp Med 2004; 199:1255-64. PubMed
  • Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C, Eck MJ. SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 2003; 5:155-60. PubMed
  • Howie D, Okamoto S, Rietdijk S, Clarke K, Wang N, Gullo C, Bruggeman JP, Manning S, Coyle AJ, Greenfield E, Kuchroo V, Terhorst C. The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon gamma production. Blood 2002; 100:2899-907. PubMed
  • Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ, Xavier RJ, Terhorst C, Podolsky DK, Bhan AK. Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice. Gastroenterology 2002; 122:134-44. PubMed
  • Poy F, Yaffe MB, Sayos J, Saxena K, Morra M, Sumegi J, Cantley LC, Terhorst C, Eck MJ. Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol Cell 1999; 4:555-61. PubMed
  • Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarolo MG, Oettgen H, De Vries JE, Aversa G, Terhorst C. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998; 395:462-9. PubMed
  • Holl. Monoallelic expression of the interleukin-2 locus. Science 1998; 279:2118-21. PubMed
  • Holl. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 1995; 373:350-3. PubMed
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