GORDON JAMES contact FREEMAN

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. ncbi Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction
    Daniel E Kaufmann
    Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Immunol 8:1246-54. 2007
  2. ncbi Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
    Fabienne Haspot
    Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Blood 112:2149-55. 2008
  3. ncbi Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade
    Shawn D Blackburn
    Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:15016-21. 2008
  4. ncbi Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade
    Gordon J Freeman
    Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    J Exp Med 203:2223-7. 2006
  5. ncbi Structures of PD-1 with its ligands: sideways and dancing cheek to cheek
    Gordon J Freeman
    Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 105:10275-6. 2008
  6. ncbi TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity
    Gordon J Freeman
    Department of Medical Oncology, Dana Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA, USA
    Immunol Rev 235:172-89. 2010
  7. ncbi Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production
    Julia A Brown
    Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 170:1257-66. 2003
  8. ncbi PD-1 on immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity
    Victor Pena-Cruz
    Department of Medical Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Invest Dermatol 130:2222-30. 2010
  9. ncbi Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade
    Erika D Reynoso
    Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 182:2102-12. 2009
  10. ncbi The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity
    Hiroshi Harada
    Department of Medicine, Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 112:234-43. 2003

Research Grants

  1. ROLE OF ICOS IN T CELL RESPONSES AND ANTI-TUMOR IMMUNITY
    Gordon Freeman; Fiscal Year: 2004
  2. TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
    GORDON JAMES contact FREEMAN; Fiscal Year: 2010

Detail Information

Publications82

  1. ncbi Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction
    Daniel E Kaufmann
    Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Immunol 8:1246-54. 2007
    ..These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients...
  2. ncbi Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
    Fabienne Haspot
    Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Blood 112:2149-55. 2008
    ..These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism...
  3. ncbi Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade
    Shawn D Blackburn
    Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:15016-21. 2008
    ..These results have implications for predicting clinical responses to PD-1-based therapeutic interventions and for understanding T cell dynamics during persisting infections...
  4. ncbi Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade
    Gordon J Freeman
    Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    J Exp Med 203:2223-7. 2006
    ..New studies now extend these observations to HIV infection and human disease...
  5. ncbi Structures of PD-1 with its ligands: sideways and dancing cheek to cheek
    Gordon J Freeman
    Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 105:10275-6. 2008
  6. ncbi TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity
    Gordon J Freeman
    Department of Medical Oncology, Dana Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA, USA
    Immunol Rev 235:172-89. 2010
    ....
  7. ncbi Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production
    Julia A Brown
    Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 170:1257-66. 2003
    ..PD-L1 is also highly expressed on most carcinomas but minimally expressed on adjacent normal tissue suggesting a role in attenuating antitumor immune responses...
  8. ncbi PD-1 on immature and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity
    Victor Pena-Cruz
    Department of Medical Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Invest Dermatol 130:2222-30. 2010
    ..Thus the PD-1 pathway is active in iLCs and inhibits iLC activities, but expression of receptor and ligands reverses upon maturation and PD-L1 and PD-L2 on mLC function to inhibit T-cell responses...
  9. ncbi Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade
    Erika D Reynoso
    Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 182:2102-12. 2009
    ..Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8(+) T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity...
  10. ncbi The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity
    Hiroshi Harada
    Department of Medicine, Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 112:234-43. 2003
    ..These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo...
  11. ncbi Critical role of CD81 in cognate T-B cell interactions leading to Th2 responses
    Jun Deng
    Division of Oncology, Department of Medicine, Stanford University Medical Center, CA 94305, USA
    Int Immunol 14:513-23. 2002
    ..Taken together, these results indicate that CD81 expression by T cells greatly enhances cognate T-B cell interactions and greatly augments intracellular activation pathways leading to Th2 polarization...
  12. ncbi Tissue expression of PD-L1 mediates peripheral T cell tolerance
    Mary E Keir
    Department of Pathology, Brigham and Women s Hospital and Children s Hospital Boston, MA 02115, USA
    J Exp Med 203:883-95. 2006
    ..These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance...
  13. ncbi PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells
    Yvette E Latchman
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 101:10691-6. 2004
    ..These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance...
  14. ncbi Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes
    Mary E Keir
    Department of Pathology, Harvard Medical School, Brigham and Women s Hospital, Boston, MA 02115 5727, USA
    J Immunol 175:7372-9. 2005
    ..These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire...
  15. ncbi TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells
    Norimoto Kobayashi
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Harvard Medical School, Boston, MA 02115, USA
    Immunity 27:927-40. 2007
    ..These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity...
  16. ncbi Cutting edge: CD94/NKG2 is expressed on Th1 but not Th2 cells and costimulates Th1 effector functions
    Jennifer Hartt Meyers
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 169:5382-6. 2002
    ..We propose that CD94/NKG2 heterodimers may costimulate effector functions of differentiated Th1 cells...
  17. ncbi Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion
    Shawn D Blackburn
    Department of Medical Oncology, Dana Farber Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Virol 84:2078-89. 2010
    ..These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway...
  18. ncbi Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice
    Diana M Brainard
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Virol 83:7305-21. 2009
    ....
  19. ncbi Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses
    Manish J Butte
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Immunity 27:111-22. 2007
    ..Our findings point to a substantial bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family...
  20. ncbi CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions
    Valerie Dardalhon
    Department of Neurology, Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Immunol 175:1558-65. 2005
    ..Our data suggest that CD226 is a costimulatory molecule that plays an important role in activation and effector functions of Th1 cells...
  21. ncbi The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival
    Linling Shen
    Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    J Immunol 179:3672-9. 2007
    ....
  22. ncbi Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses
    Spencer C Liang
    Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
    Eur J Immunol 33:2706-16. 2003
    ..PD-L2, but not PD-L1, expression was dramatically reduced in p50(-/-)p65(+/-) DC. Thus, PD-L1 and PD-L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level...
  23. ncbi Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity
    Hyun Hee Lee
    Division of Immunology and Allergy, Department of Pediatrics, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 185:5225-35. 2010
    ..Furthermore, these results provide evidence for a novel innate pathway that results in airway hyperreactivity and may help to explain how TIM-1 and NKT cells regulate asthma...
  24. ncbi PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis
    Spencer C Liang
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Eur J Immunol 36:58-64. 2006
    ..Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana...
  25. ncbi PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues
    Mary E Keir
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    J Immunol 179:5064-70. 2007
    ....
  26. ncbi Role of PD-1 in regulating acute infections
    Keturah E Brown
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Curr Opin Immunol 22:397-401. 2010
    ..Thus, PD-1 can influence adaptive immune responses during acute infections, though precisely how this regulation occurs is only just beginning to be appreciated...
  27. ncbi CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator
    Guifang Cai
    Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Immunol 9:176-85. 2008
    ..CD160 thus serves as a negative regulator of CD4+ T cell activation through its interaction with HVEM...
  28. ncbi Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance
    Catherine A Sabatos
    Department of Neurology, Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Immunol 4:1102-10. 2003
    ..These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector T(H)1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance...
  29. ncbi Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis
    Nancy Rodig
    The Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
    Eur J Immunol 33:3117-26. 2003
    ..Our findings highlight a potentially important pathway by which endothelial cells down-regulate CD8+ T cell-mediated immune responses...
  30. ncbi Interaction of human PD-L1 and B7-1
    Manish J Butte
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Mol Immunol 45:3567-72. 2008
    ..We show that PD-L1 is induced to a higher level on CD28high T cells than on CD28low T cells upon activation. These results suggest that PD-L1 may play an important and undervalued role on human T cells...
  31. ncbi PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells
    Guifang Cai
    Laboratory of Molecular Immunology, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA
    Cell Immunol 230:89-98. 2004
    ..Together, our data demonstrated PD-1 functioned as a negative regulatory pathway on naive T cells during a primary response, and more potently, on memory or recently activated T cells during a secondary response...
  32. ncbi Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-beta signaling in activated T lymphocytes
    Dimitrios Tzachanis
    Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
    Blood 109:2944-52. 2007
    ..Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases...
  33. ncbi The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection
    Arlene H Sharpe
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nat Immunol 8:239-45. 2007
    ..Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway...
  34. ncbi Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease
    Laurent Monney
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 415:536-41. 2002
    ..Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function...
  35. ncbi Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation
    De xiu Bu
    Department of Pathology, Brigham and Women s Hospital, and Department of Medicine, Harvard Medical School, NRB Rm 752N, 77 Ave Louis Pasteur, Boston, MA 02115, USA
    Arterioscler Thromb Vasc Biol 31:1100-7. 2011
    ..We studied the contribution of the PD-1 pathway to regulation of T cells that promote atherosclerotic lesion formation and inflammation...
  36. ncbi A novel alloantigen-specific CD8+PD1+ regulatory T cell induced by ICOS-B7h blockade in vivo
    Atsushi Izawa
    Transplantation Research Center, Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Immunol 179:786-96. 2007
    ..These results describe a novel allospecific regulatory CD8(+)PD1(+) T cell induced by ICOS-B7h blockade in vivo...
  37. ncbi ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival
    Omid Akbari
    Division of Immunology, Children s Hospital, Harvard Medical School, Boston, MA, 02115, USA
    J Immunol 180:5448-56. 2008
    ..These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4(+) iNKT cell function, homeostasis, and survival in the periphery...
  38. ncbi The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation
    Guifang Cai
    Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Immunol Rev 229:244-58. 2009
    ..Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding are being developed to enhance immune responses and vaccination...
  39. ncbi Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye-associated corneal inflammation
    Jaafar El Annan
    Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
    Invest Ophthalmol Vis Sci 51:3418-23. 2010
    ..Downregulation of corneal epithelial PD-L1 amplifies dry eye-associated corneal inflammation and epitheliopathy by increasing the expression of chemokine ligands and receptors that promote T-cell homing to the ocular surface...
  40. ncbi CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo
    Clare Baecher-Allan
    Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
    Novartis Found Symp 252:67-88; discussion 88-91, 106-14. 2003
    ....
  41. ncbi Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity
    Naoto Hirano
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA
    Blood 107:1528-36. 2006
    ..Therefore, engagement of the CD83L provides a unique signal to activated CD8+ T cells that could be exploited to generate long-lived antigen-specific cytotoxic T cells for the treatment of cancer and infection...
  42. ncbi The B7 family revisited
    Rebecca J Greenwald
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Annu Rev Immunol 23:515-48. 2005
    ..In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential...
  43. ncbi The B7-CD28 superfamily
    Arlene H Sharpe
    Immunology Research Division, Department of Pathology, Brigham, and Women s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA
    Nat Rev Immunol 2:116-26. 2002
    ..Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential...
  44. ncbi The TIM gene family: emerging roles in immunity and disease
    Vijay K Kuchroo
    Center for Neurologic Diseases, Brigham and Women s Hospital, Dana Farber Cancer Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
    Nat Rev Immunol 3:454-62. 2003
    ..Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases...
  45. ncbi Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells
    Xueli Yuan
    Transplantation Research Center, Renal Division, Brigham and Women s Hospital and Children s Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 106:10734-9. 2009
    ..These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation...
  46. ncbi Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors
    Mathias Lichterfeld
    Partners AIDS Research Center and Harvard University Center for AIDS Research, Massachusetts General Hospital, Boston, MA, USA
    Blood 112:3679-87. 2008
    ....
  47. ncbi Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization
    Nobuhiro Nakamoto
    Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Gastroenterology 134:1927-37, 1937.e1-2. 2008
    ..As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD-1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients...
  48. ncbi RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion
    Esther M Lafuente
    Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Dev Cell 7:585-95. 2004
    ..RIAM knockdown displaced Rap1-GTP from the plasma membrane and abrogated Rap1-induced adhesion. Thus, RIAM links Rap1 to integrin activation and plays a role in regulating actin dynamics...
  49. ncbi PD-1 and its ligands in tolerance and immunity
    Mary E Keir
    Department of Pathology, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115 5727, USA
    Annu Rev Immunol 26:677-704. 2008
    ..In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential...
  50. ncbi The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity
    Kunihiko Takeyama
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA
    J Biol Chem 278:21930-7. 2003
    ..Consistent with this idea, BBAP and DTX1 associate via their unique N termini, resulting in enhanced self-ubiquitination...
  51. ncbi Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart
    Nir Grabie
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Circulation 116:2062-71. 2007
    ..PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart...
  52. ncbi Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF
    Michael Quigley
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 16:1147-51. 2010
    ..Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV...
  53. ncbi PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
    Loise M Francisco
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    J Exp Med 206:3015-29. 2009
    ..These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity...
  54. ncbi Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo
    Lequn Li
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
    J Immunol 175:3133-9. 2005
    ....
  55. ncbi T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells
    Rosemarie H DeKruyff
    Division of Immunology, Children s Hospital Boston, E, Boston, MA, USA
    J Immunol 184:1918-30. 2010
    ..These findings establish a new paradigm for TIM proteins as PtdSer receptors and unify the function of the TIM gene family, which has been associated with asthma and autoimmunity and shown to modulate peripheral tolerance...
  56. ncbi Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1
    Nadine C Salisch
    Division of Immunology, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA
    J Immunol 184:476-87. 2010
    ....
  57. ncbi The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms
    David M Dorfman
    Department of Pathology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Hum Pathol 41:1486-94. 2010
    ..We conclude that histiocytic and dendritic cell neoplasms consistently express TIM-3 and TIM-4 and that these molecules are new markers of neoplasms derived from histiocytic and dendritic cells...
  58. ncbi Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma
    David M Dorfman
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    Am J Surg Pathol 30:802-10. 2006
    ....
  59. ncbi Simian immunodeficiency virus (SIV)-specific CD8+ T-cell responses in vervet African green monkeys chronically infected with SIVagm
    Roland C Zahn
    Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
    J Virol 82:11577-88. 2008
    ..These observations demonstrate that natural hosts like SIV-infected vervet AGM develop SIV-specific T-cell responses, but the disease-free course of infection does not depend on the generation of robust CD8(+) T-cell responses...
  60. ncbi CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion
    Ann E Herman
    Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA
    J Exp Med 199:1479-89. 2004
    ..Thus, CD4+CD25+69- Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state...
  61. ncbi Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response
    Arnon Karni
    Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Havard Medical School, Boston, MA 02115-5817, USA
    J Immunol 177:4196-202. 2006
    ..These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS...
  62. ncbi PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver
    Holly Maier
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    J Immunol 178:2714-20. 2007
    ..Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism...
  63. ncbi Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells
    Michael J Eppihimer
    Discovery Research Respiratory Diseases, Wyeth Genetics Institute, Andover, MA 01810, USA
    Microcirculation 9:133-45. 2002
    ..To evaluate the expression and regulation of a novel B7-like protein, PD-L1, the ligand for the immunoinhibitory receptor PD-1 expressed on activated T-cells, on microvascular endothelial cells (ECs)..
  64. ncbi Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues
    Masayoshi Ishida
    Laboratory of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606 8501, Japan
    Immunol Lett 84:57-62. 2002
    ..Thus, present results demonstrate the distinct expression patterns of PD-L1 and PD-L2 with the cells of lymphohematopoietic tissues exclusively expressing the former...
  65. ncbi Protect the killer: CTLs need defenses against the tumor
    Gordon J Freeman
    Nat Med 8:787-9. 2002
  66. ncbi PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2
    LauraL Carter
    Wyeth Genetics Institute, Cambridge, MA 02140, USA
    Eur J Immunol 32:634-43. 2002
    ..However, CD8(+) T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2...
  67. ncbi Immunology: hepatitis A virus link to atopic disease
    Jennifer J McIntire
    Division of Immunology and Allergy, Department of Pediatrics, Stanford University, Stanford, California 94305-5208, USA
    Nature 425:576. 2003
  68. ncbi Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity
    Omid Akbari
    Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, USA
    Nat Med 8:1024-32. 2002
    ..These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma...
  69. ncbi Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection
    Sang Jun Ha
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Exp Med 205:543-55. 2008
    ..Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors...
  70. ncbi PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
    Cheryl L Day
    HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa
    Nature 443:350-4. 2006
    ..Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection...
  71. ncbi The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system
    Xuesong Qian
    Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
    Eur J Immunol 36:906-18. 2006
    ....
  72. ncbi Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection
    Scott N Mueller
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
    Proc Natl Acad Sci U S A 104:15430-5. 2007
    ..These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection...
  73. ncbi PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status
    Delphine Sauce
    Cellular Immunology Laboratory, INSERM U543, Avenir Group, Hopital Pitie Salpetriere, Universite Pierre et Marie Curie Paris 6, Paris, France
    AIDS 21:2005-13. 2007
    ..Assessing PD-1 expression on T cells may be highly relevant in T-cell immunology and vaccine monitoring. However, this requires us to gain further insights into the significance of PD-1 expression on CD8 T cells in humans...
  74. ncbi TIM-1 induces T cell activation and inhibits the development of peripheral tolerance
    Sarah E Umetsu
    Department of Pediatrics, Stanford University, Stanford, California 94305, USA
    Nat Immunol 6:447-54. 2005
    ..Our studies suggest that immunotherapies that regulate TIM-1 function may downmodulate allergic inflammatory diseases...
  75. ncbi Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds
    Cesar Santiago
    Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autonoma, 28049 Madrid, Spain
    Immunity 27:941-51. 2007
    ..Our results also revealed an important role of the MILIBS in the trafficking of TIM-1 to the cell surface...
  76. ncbi Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM)
    Patricia A Taylor
    University of Minnesota Cancer Center and Department of Pediatrics, Division of BMT, Minneapolis, MN 55455, USA
    Blood 105:3372-80. 2005
    ..These data suggest that the ICOS pathway may be a beneficial therapeutic target for GVHD inhibition, GVHD therapy, and BM graft promotion...
  77. ncbi The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum
    Eszter Lazar-Molnar
    Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Proc Natl Acad Sci U S A 105:2658-63. 2008
    ..The results show that the PD-1/PD-L pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis...
  78. ncbi Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice
    Baowei Peng
    Department of Pediatrics, Seattle Children s Hospital Research Institute and University of Washington, Seattle, WA 98101, USA
    Blood 112:1662-72. 2008
    ..Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy...
  79. ncbi Restoring function in exhausted CD8 T cells during chronic viral infection
    Daniel L Barber
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Nature 439:682-7. 2006
    ..These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections...
  80. ncbi An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells
    Lalitha Vijayakrishnan
    Center for Neurologic Diseases, Department of Neurology, Boston, MA 02115 USA
    Immunity 20:563-75. 2004
    ..These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases...
  81. ncbi Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection
    Henry Radziewicz
    Emory University School of Medicine, 954 Gatewood Road, NE, Atlanta, GA 30329, USA
    J Virol 82:9808-22. 2008
    ..This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections...
  82. ncbi Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions
    Cecilia Tami
    Laboratory of Hepatitis and Related Emerging Agents, CBER, Food and Drug Administration, Bethesda, MD 20892, USA
    J Virol 81:3437-46. 2007
    ..IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1lambda is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions...

Research Grants6

  1. ROLE OF ICOS IN T CELL RESPONSES AND ANTI-TUMOR IMMUNITY
    Gordon Freeman; Fiscal Year: 2004
    ..To examine the expression the expression of ICOS counter-receptor on APC and characterize its molecular structure. SPECIFIC AIM 3. To examine how blocking ICOS signals affect the immune response to murine tumors. ..
  2. TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
    GORDON JAMES contact FREEMAN; Fiscal Year: 2010
    ..TIM proteins recognize dead cells and help remove them from the body. Increased understanding of how TIM proteins regulate immune responses will allow us to design therapies for asthma, allergies, autoimmune disease and cancer. ..