Photo of Gordon J. Freeman,  PhD

Gordon J. Freeman, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4585
Fax: (617) 632-5167


gordon_freeman@dfci.harvard.edu

Gordon J. Freeman, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory studies the role of costimulatory signals in the development of an immune response. T cell activation requires two signals. Specificity is provided by TCR recognition of peptide-MHC complexes but a second, costimulatory signal is required for full T cell activation. The B7 gene family, comprised of B7-1 and B7-2, provide the critical costimulatory signal for full T cell activation, clonal expansion, and development of effector function through their interaction with CD28 on T cells. After T cell activation, the interaction of B7-1 and B7-2 with the higher affinity ligand, CTLA4, expressed on activated T cells, leads to down-regulation of T cell activation. Stimulation of the TCR alone leads to T cell clonal anergy thus blockade of B7-1 and B7-2 can be used to establish antigen-specific tolerance for transplantation or the alleviation of autoimmunity. Conversely, expression of B7-1 and B7-2 can stimulate an immune response and the introduction of B7-1 or B7-2 into tumors can stimulate an anti-tumor response leading to tumor rejection and anti-tumor immunity. Recently, we have cloned two novel members of the B7 gene family. These new B7s bind to receptors expressed on activated T cells and further regulate the development of an immune response. We are currently focusing on the function of these novel B7 genes and their interactions with the B7/CD28-CTLA4 pathway.

Publications

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  • Mahoney KM, Freeman GJ, McDermott DF. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther 2015. PubMed
  • Balan M, Mier Y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, Pal S. Novel Roles of c-Met in the Survival of Renal Cancer Cells through the Regulation of HO-1 and PD-L1 Expression. J Biol Chem 2015; 290:8110-20. PubMed
  • Veenstra RG, Flynn R, Kreymborg K, McDonald-Hyman C, Saha A, Taylor PA, Osborn MJ, Panoskaltsis-Mortari A, Schmitt-Graeff A, Lieberknect E, Murphy WJ, Serody JS, Munn DH, Freeman GJ, Allison JP, Mak TW, van den Brink M, Zeiser R, Blazar BR. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood 2015. PubMed
  • Goldberg J, Fisher DE, Demetri GD, Neuberg D, Allsop S, Fonseca C, Nakazaki Y, Nemer D, Raut CP, George S, Morgan JA, Wagner AJ, Freeman GJ, Ritz J, Lezcano C, Mihm MC, Canning C, Hodi FS, Dranoff G. Biologic Activity of Autologous, Granulocyte-Macrophage Colony Stimulating Factor Secreting Alveolar Soft Parts Sarcoma and Clear Cell Sarcoma Vaccines. Clin Cancer Res 2015. PubMed
  • Maazi H, Patel N, Sankaranarayanan I, Suzuki Y, Rigas D, Soroosh P, Freeman GJ, Sharpe AH, Akbari O. ICOS:ICOS-Ligand Interaction Is Required for Type 2 Innate Lymphoid Cell Function, Homeostasis, and Induction of Airway Hyperreactivity. Immunity 2015; 42:538-51. PubMed
  • Du Z, Abedalthagafi M, Aizer AA, McHenry AR, Sun HH, Bray MA, Viramontes O, Machaidze R, Brastianos PK, Reardon DA, Dunn IF, Freeman GJ, Ligon KL, Carpenter AE, Alexander BM, Agar NY, Rodig SJ, Bradshaw EM, Santagata S. Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. 2015; 6:4704-16. PubMed
  • Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372:311-9. PubMed
  • Fay AP, Signoretti S, Callea M, Telό GH, McKay RR, Song J, Carvo I, Lampron ME, Kaymakcalan MD, Poli-de-Figueiredo CE, Bellmunt J, Hodi FS, Freeman GJ, Elfiky A, Choueiri TK. Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer 2015; 3:3. PubMed
  • Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6:6692. PubMed
  • Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. 2015; 5:16-8. PubMed
  • Cooper ZA, Juneja VR, Sage PT, Frederick DT, Piris A, Mitra D, Lo JA, Hodi FS, Freeman GJ, Bosenberg MW, McMahon M, Flaherty KT, Fisher DE, Sharpe AH, Wargo JA. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res 2014. PubMed
  • Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, Reibel JB, Walton Z, Ji H, Watanabe H, Jänne PA, Castrillon DH, Rustgi AK, Bass AJ, Freeman GJ, Padera RF, Dranoff G, Hammerman PS, Kim CF, Wong KK. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014; 25:590-604. PubMed
  • Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, Freeman GJ, Serody JS, Murphy WJ, Munn DH, Sarantopoulos S, Luznik L, Maillard I, Koreth J, Cutler C, Soiffer RJ, Antin JH, Ritz J, Dubovsky JA, Byrd JC, Macdonald KP, Hill GR, Blazar BR. Increased T follicular helper cells and germinal center B cells are required for chronic GVHD (cGVHD) and bronchiolitis obliterans. Blood 2014. PubMed
  • Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, Hua P, Duke-Cohan JS, Umetsu DT, Sharpe AH, DeKruyff RH, Freeman GJ. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 2014. PubMed
  • Kroy DC, Ciuffreda D, Cooperrider JH, Tomlinson M, Hauck GD, Aneja J, Berger C, Wolski D, Carrington M, Wherry EJ, Chung RT, Tanabe KK, Elias N, Freeman GJ, de Kruyff RH, Misdraji J, Kim AY, Lauer GM. Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 2014; 146:550-61. PubMed
  • Duraiswamy J, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--response. Cancer Res 2014; 74:633-4; discussion 635. PubMed
  • Mott KR, Allen SJ, Zandian M, Akbari O, Hamrah P, Maazi H, Wechsler SL, Sharpe AH, Freeman GJ, Ghiasi H. Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS ONE 2014; 9:e87617. PubMed
  • Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, Wilkerson MD, Fecci PE, Butaney M, Reibel JB, Soucheray M, Cohoon TJ, Janne PA, Meyerson M, Hayes DN, Shapiro GI, Shimamura T, Sholl LM, Rodig SJ, Freeman GJ, Hammerman PS, Dranoff G, Wong KK. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. 2013. PubMed
  • Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 2013; 73:6900-12. PubMed
  • Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, Munn DH, Murphy WJ, Azuma M, Yagita H, Fife BT, Sayegh MH, Najafian N, Socie G, Ahmed R, Freeman GJ, Sharpe AH, Blazar BR. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood 2013; 122:3062-73. PubMed
  • Fuller MJ, Callendret B, Zhu B, Freeman GJ, Hasselschwert DL, Satterfield W, Sharpe AH, Dustin LB, Rice CM, Grakoui A, Ahmed R, Walker CM. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 2013; 110:15001-6. PubMed
  • Kim HY, Chang YJ, Chuang YT, Lee HH, Kasahara DI, Martin T, Hsu JT, Savage PB, Shore SA, Freeman GJ, Dekruyff RH, Umetsu DT. T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death. J Allergy Clin Immunol 2013; 132:414-25.e6. PubMed
  • Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19:3462-73. PubMed
  • Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 2013; 73:3591-603. PubMed
  • Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY, Curry WT, Mitchell DA, Fecci PE, Sampson JH, Dranoff G. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. 2013; 12:597-615. PubMed
  • Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, Freeman GJ, Krogsgaard M, Riley JL. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A 2013. PubMed
  • D'Addio F, Ueno T, Clarkson M, Zhu B, Vergani A, Freeman GJ, Sayegh MH, Ansari MJ, Fiorina P, Habicht A. CD160Ig Fusion Protein Targets a Novel Costimulatory Pathway and Prolongs Allograft Survival. PLoS ONE 2013; 8:e60391. PubMed
  • Chou CK, Schietinger A, Liggitt HD, Tan X, Funk S, Freeman GJ, Ratliff TL, Greenberg NM, Greenberg PD. Cell-Intrinsic Abrogation of TGF-硫 Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer. J Immunol 2012; 189:3936-46. PubMed
  • Naito M, Hainz U, Burkhardt UE, Fu B, Ahove D, Stevenson KE, Rajasagi M, Zhu B, Alonso A, Witten E, Matsuoka KI, Neuberg D, Duke-Cohan JS, Wu CJ, Freeman GJ. CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother 2012. PubMed
  • Bu DX, Tarrio M, Maganto-Garcia E, Stavrakis G, Tajima G, Lederer J, Jarolim P, Freeman GJ, Sharpe AH, Lichtman AH. Impairment of the Programmed Cell Death-1 Pathway Increases Atherosclerotic Lesion Development and Inflammation. Arterioscler Thromb Vasc Biol 2011. PubMed
  • Allen SJ, Hamrah P, Gate DM, Mott KR, Mantopoulos D, Zheng L, Town T, Jones C, von Andrian UH, Freeman GJ, Sharpe AH, Benmohamed L, Ahmed R, Wechsler SL, Ghiasi H. The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus type 1. J Virol 2011. PubMed
  • Albacker LA, Karisola P, Chang YJ, Umetsu SE, Zhou M, Akbari O, Kobayashi N, Baumgarth N, Freeman GJ, Umetsu DT, DeKruyff RH. TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells. J Immunol 2010; 185:6839-49. PubMed
  • Flutter B, Edwards N, Fallah-Arani F, Henderson S, Chai JG, Sivakumaran S, Ghorashian S, Bennett CL, Freeman GJ, Sykes M, Chakraverty R. Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J Clin Invest 2010; 120:3855-68. PubMed
  • Dorfman DM, Hornick JL, Shahsafaei A, Freeman GJ. The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms. Hum Pathol 2010; 41:1486-94. PubMed
  • Peña-Cruz V, McDonough SM, Diaz-Griffero F, Crum CP, Carrasco RD, Freeman GJ. PD-1 on Immature and PD-1 Ligands on Migratory Human Langerhans Cells Regulate Antigen-Presenting Cell Activity. J Invest Dermatol 2010; 130:2222-30. PubMed
  • El Annan J, Goyal S, Zhang Q, Freeman GJ, Sharpe AH, Dana R. Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye-associated corneal inflammation. Invest Ophthalmol Vis Sci 2010; 51:3418-23. PubMed
  • Brown KE, Freeman GJ, Wherry EJ, Sharpe AH. Role of PD-1 in regulating acute infections. Curr Opin Immunol 2010; 22:397-401. PubMed
  • Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 2010; 235:172-89. PubMed
  • DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 2010; 184:1918-30. PubMed
  • Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol 2010; 84:2078-89. PubMed
  • Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206:3015-29. PubMed
  • Currie AJ, Prosser A, McDonnell A, Cleaver AL, Robinson BW, Freeman GJ, van der Most RG. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol 2009; 183:7898-908. PubMed
  • Chen L,Sham CW,Chan AM,Francisco LM,Wu Y,Mareninov S,Sharpe AH,Freeman G,Yang XJ,Braun J,Gordon LK. Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells. Invest Ophthalmol Vis Sci 2009; 50:4941-8. PubMed
  • Sauce D, Larsen M, Abbott RJ, Hislop AD, Leese AM, Khan N, Papagno L, Freeman GJ, Rickinson AB. Upregulation of interleukin 7 receptor alpha and programmed death 1 marks an epitope-specific CD8+ T-cell response that disappears following primary Epstein-Barr virus infection. J Virol 2009; 83:9068-78. PubMed
  • Brainard DM,Seung E,Frahm N,Cariappa A,Bailey CC,Hart WK,Shin HS,Brooks SF,Knight HL,Eichbaum Q,Yang YG,Sykes M,Walker BD,Freeman GJ,Pillai S,Westmoreland SV,Brander C,Luster AD,Tager AM. Induction of robust cellular and humoral virus-specific adaptive immune responses in HIV-infected humanized BLT mice. J Virol 2009; 83:7305-21. PubMed
  • Yuan X, Ansari MJ, D'Addio F, Paez-Cortez J, Schmitt I, Donnarumma M, Boenisch O, Zhao X, Popoola J, Clarkson MR, Yagita H, Akiba H, Freeman GJ, Iacomini J, Turka LA, Glimcher LH, Sayegh MH. Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A 2009; 106:10734-9. PubMed
  • Cai G,Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 2009; 229:244-58. PubMed
  • Velu V,Titanji K,Zhu B,Husain S,Pladevega A,Lai L,Vanderford TH,Chennareddi L,Silvestri G,Freeman GJ,Ahmed R,Amara RR. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2008; 458:206-10. PubMed
  • Reynoso ED,Elpek KG,Francisco L,Bronson R,Bellemare-Pelletier A,Sharpe AH,Freeman GJ,Turley SJ. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 2009; 182:2102-12. PubMed
  • Nakamoto N,Cho H,Shaked A,Olthoff K,Valiga ME,Kaminski M,Gostick E,Price DA,Freeman GJ,Wherry EJ,Chang KM. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 2009; 5:e1000313. PubMed
  • Blackburn SD,Shin H,Haining WN,Zou T,Workman CJ,Polley A,Betts MR,Freeman GJ,Vignali DA,Wherry EJ. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2008; 10:29-37. PubMed
  • Chen L,Pai V,Levinson R,Sharpe AH,Freeman GJ,Braun J,Gordon LK. Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis. Ocul Immunol Inflamm 2009; 17:47-55. PubMed
  • Brooks DG,Ha SJ,Elsaesser H,Sharpe AH,Freeman GJ,Oldstone MB. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci U S A 2008; 105:20428-33. PubMed
  • Zahn RC,Rett MD,Korioth-Schmitz B,Sun Y,Buzby AP,Goldstein S,Brown CR,Byrum RA,Freeman GJ,Letvin NL,Hirsch VM,Schmitz JE. Simian immunodeficiency virus (SIV)-specific CD8+ T-cell responses in vervet African green monkeys chronically infected with SIVagm. J Virol 2008; 82:11577-88. PubMed
  • Lichterfeld M,Mou D,Cung TD,Williams KL,Waring MT,Huang J,Pereyra F,Trocha A,Freeman GJ,Rosenberg ES,Walker BD,Yu XG. 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. Blood 2008; 112:3679-87. PubMed
  • Radziewicz H,Ibegbu CC,Hon H,Osborn MK,Obideen K,Wehbi M,Freeman GJ,Lennox JL,Workowski KA,Hanson HL,Grakoui A. 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. J Virol 2008; 82:9808-22. PubMed
  • Blackburn SD,Shin H,Freeman GJ,Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 2008; 105:15016-21. PubMed
  • Haspot F,Fehr T,Gibbons C,Zhao G,Hogan T,Honjo T,Freeman GJ,Sykes M. Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway. Blood 2008; 112:2149-55. PubMed
  • Butte MJ,Pena-Cruz V,Kim MJ,Freeman GJ,Sharpe AH. Interaction of human PD-L1 and B7-1. Mol Immunol 2008; 45:3567-72. PubMed
  • Freeman GJ. Structures of PD-1 with its ligands: sideways and dancing cheek to cheek. Proc Natl Acad Sci U S A 2008; 105:10275-6. PubMed
  • Nakamoto N,Kaplan DE,Coleclough J,Li Y,Valiga ME,Kaminski M,Shaked A,Olthoff K,Gostick E,Price DA,Freeman GJ,Wherry EJ,Chang KM. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 2008; 134:1927-37, 1937.e1-2. PubMed
  • Bowen DG, Shoukry NH, Grakoui A, Fuller MJ, Cawthon AG, Dong C, Hasselschwert DL, Brasky KM, Freeman GJ, Seth NP, Wucherpfennig KW, Houghton M, Walker CM. Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection. J Virol 2008; 82:5109-14. PubMed
  • Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. Corrigendum: CD160 inhibits activation of human CD4(+) T cells through interaction with herpesvirus entry mediator. Nat Immunol 2008; 9:567. PubMed
  • Akbari O, Stock P, Meyer EH, Freeman GJ, Sharpe AH, Umetsu DT, DeKruyff RH. ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival. J Immunol 2008; 180:5448-56. PubMed
  • Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and Its Ligands in Tolerance and Immunity. Annu Rev Immunol 2008; 26:677-704. PubMed
  • Ha SJ, Mueller SN, Wherry EJ, Barber DL, Aubert RD, Sharpe AH, Freeman GJ, Ahmed R. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med 2008; 205:543-55. PubMed
  • Lazar-Molnar E, Gacser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD. The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci U S A 2008; 105:2658-63. PubMed
  • Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol 2008; 9:176-85. PubMed
  • Ansari MJ, Fiorina P, Dada S, Guleria I, Ueno T, Yuan X, Trikudanathan S, Smith RN, Freeman G, Sayegh MH. Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice. Clin Immunol 2007; 126:140-7. PubMed
  • Kobayashi N, Karisola P, Pe. TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic Cells. Immunity 2007; 27:927-40. PubMed
  • Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 2007; 8:1246-54. PubMed
  • Keir ME, Freeman GJ, Sharpe AH. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol 2007; 179:5064-70. PubMed
  • Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, Appay V. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS 2007; 21:2005-13. PubMed
  • Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, Gangappa S, Larsen CP, Ahmed R. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci U S A 2007; 104:15430-5. PubMed
  • Shen L, Jin Y, Freeman GJ, Sharpe AH, Dana MR. The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival. J Immunol 2007; 179:3672-9. PubMed
  • Izawa A, Yamaura K, Albin MJ, Jurewicz M, Tanaka K, Clarkson MR, Ueno T, Habicht A, Freeman GJ, Yagita H, Abdi R, Pearson T, Greiner DL, Sayegh MH, Najafian N. A novel alloantigen-specific CD8+PD1+ regulatory T cell induced by ICOS-B7h blockade in vivo. J Immunol 2007; 179:786-96. PubMed
  • Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27:111-22. PubMed
  • Velu V, Kannanganat S, Ibegbu C, Chennareddi L, Villinger F, Freeman GJ, Ahmed R, Amara RR. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol 2007; 81:5819-28. PubMed
  • Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2006; 30:802-10. PubMed
  • Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 2006; 203:883-95. PubMed
  • Qian X, Agematsu K, Freeman GJ, Tagawa Y, Sugane K, Hayashi T. The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system. Eur J Immunol 2006; 36:906-18. PubMed
  • Hirano N, Butler MO, Xia Z, Ans. Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity. Blood 2005; 107:1528-36. PubMed
  • Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2005; 439:682-7. PubMed
  • Liang SC, Greenwald RJ, Latchman YE, Rosas L, Satoskar A, Freeman GJ, Sharpe AH. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur J Immunol 2005; 36:58-64. PubMed
  • Taylor PA, Panoskaltsis-Mortari A, Freeman GJ, Sharpe AH, Noelle RJ, Rudensky AY, Mak TW, Serody JS, Blazar BR. 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). Blood 2004; 105:3372-80. PubMed
  • Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, Kuchroo VK, Freeman GJ, Sharpe AH. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci U S A 2004; 101:10691-6. PubMed
  • Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004; 199:1479-89. PubMed
  • Vijayakrishnan L, Slavik JM, Ill. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 2004; 20:563-75. PubMed
  • Sabatos CA, Chakravarti S, Cha E, Schubart A, S. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 2003; 4:1102-10. PubMed
  • Rodig N, Ryan T, Allen JA, Pang H, Grabie N, Chernova T, Greenfield EA, Liang SC, Sharpe AH, Lichtman AH, Freeman GJ. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 2003; 33:3117-26. PubMed
  • Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, Sharpe AH. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003; 33:2706-16. PubMed
  • Harada H, Salama AD, Sho M, Izawa A, Sandner SE, Ito T, Akiba H, Yagita H, Sharpe AH, Freeman GJ, Sayegh MH. The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest 2003; 112:234-43. PubMed
  • Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA. The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem 2003; 278:21930-7. PubMed
  • Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo. Novartis Found Symp 2003; 252:67-88; discussion 88-91,. PubMed
  • Meyers JH, Ryu A, Monney L, Nguyen K, Greenfield EA, Freeman GJ, Kuchroo VK. Cutting edge: CD94/NKG2 is expressed on Th1 but not Th2 cells and costimulates Th1 effector functions. J Immunol 2002; 169:5382-6. PubMed
  • Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002; 8:1024-32. PubMed
  • Freeman GJ, Sharpe AH, Kuchroo VK. Protect the killer: CTLs need defenses against the tumor. Nat Med 2002; 8:787-9. PubMed
  • Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002; 2:116-26. PubMed
  • Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415:536-41. PubMed
  • Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A, Nadler LM, Boussiotis VA. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol 2001; 2:1174-82. PubMed
  • McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, Freeman GJ, Umetsu DT, DeKruyff RH. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2001; 2:1109-16. PubMed
  • Gaglia JL, Mattoo A, Greenfield EA, Freeman GJ, Kuchroo VK. Characterization of endogenous Chinese hamster ovary cell surface molecules that mediate T cell costimulation. Cell Immunol 2002; 213:83-93. PubMed
  • Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001; 167:1245-53. PubMed
  • Datta MW, Shahsafaei A, Nadler LM, Freeman GJ, Dorfman DM. Expression of MHC class II-associated invariant chain (Ii;CD74) in thymic epithelial neoplasms. Appl Immunohistochem Mol Morphol 2000; 8:210-5. PubMed
  • Boussiotis VA, Freeman GJ, Taylor PA, Berezovskaya A, Grass I, Blazar BR, Nadler LM. p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes. Nat Med 2000; 6:290-7. PubMed
  • Aguiar RC, Yakushijin Y, Kharbanda S, Tiwari S, Freeman GJ, Shipp MA. PTPROt: an alternatively spliced and developmentally regulated B-lymphoid phosphatase that promotes G0/G1 arrest. Blood 1999; 94:2403-13. PubMed
  • Stremmel C, Greenfield EA, Howard E, Freeman GJ, Kuchroo VK. B7-2 expressed on EL4 lymphoma suppresses antitumor immunity by an interleukin 4-dependent mechanism. J Exp Med 1999; 189:919-30. PubMed
  • Agrawal S, Marquet J, Freeman GJ, Tawab A, Bouteiller PL, Roth P, Bolton W, Ogg G, Boumsell L, Bensussan A. Cutting edge: MHC class I triggering by a novel cell surface ligand costimulates proliferation of activated human T cells. J Immunol 1999; 162:1223-6. PubMed
  • Anumanthan A, Bensussan A, Boumsell L, Christ AD, Blumberg RS, Voss SD, Patel AT, Robertson MJ, Nadler LM, Freeman GJ. Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes. J Immunol 1998; 161:2780-90. PubMed
  • Freeman GJ, Cardoso AA, Boussiotis VA, Anumanthan A, Groves RW, Kupper TS, Clark EA, Nadler LM. The BB1 monoclonal antibody recognizes both cell surface CD74 (MHC class II-associated invariant chain) as well as B7-1 (CD80), resolving the question regarding a third CD28/CTLA-4 counterreceptor. J Immunol 1998; 161:2708-15. PubMed
  • Duke-Cohan JS, Gu J, McLaughlin DF, Xu Y, Freeman GJ, Schlossman SF. Attractin (DPPT-L), a member of the CUB family of cell adhesion and guidance proteins, is secreted by activated human T lymphocytes and modulates immune cell interactions. Proc Natl Acad Sci U S A 1998; 95:11336-41. PubMed
  • Dorfman DM, Shahsafaei A, Nadler LM, Freeman GJ. The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas. Am J Pathol 1998; 153:255-62. PubMed
  • Scholz C, Patton KT, Anderson DE, Freeman GJ, Hafler DA. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. J Immunol 1998; 160:1532-8. PubMed
  • Dorfman DM, Schultze JL, Shahsafaei A, Michalak S, Gribben JG, Freeman GJ, Pinkus GS, Nadler LM. In vivo expression of B7-1 and B7-2 by follicular lymphoma cells can prevent induction of T-cell anergy but is insufficient to induce significant T-cell proliferation. Blood 1997; 90:4297-306. PubMed
  • Boussiotis VA, Freeman GJ, Berezovskaya A, Barber DL, Nadler LM. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1. Science 1997; 278:124-8. PubMed
  • Anderson DE, Ausubel LJ, Krieger J, H. Weak peptide agonists reveal functional differences in B7-1 and B7-2 costimulation of human T cell clones. J Immunol 1997; 159:1669-75. PubMed
  • Borriello F, Sethna MP, Boyd SD, Schweitzer AN, Tivol EA, Jacoby D, Strom TB, Simpson EM, Freeman GJ, Sharpe AH. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 1997; 6:303-13. PubMed
  • Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM, Freeman GJ. Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci U S A 1996; 93:11780-5. PubMed
  • Freeman GJ, Boussiotis VA, Anumanthan A, Bernstein GM, Ke XY, Rennert PD, Gray GS, Gribben JG, Nadler LM. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 1995; 2:523-32. PubMed
  • Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA, Ke X, Gray GS. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A 1995; 92:811-5. PubMed
  • Sethna MP, van Parijs L, Sharpe AH, Abbas AK, Freeman GJ. A negative regulatory function of B7 revealed in B7-1 transgenic mice. Immunity 1994; 1:415-21. PubMed
  • Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA, Lombard LA, Gray GS, Nadler LM. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 1993; 262:909-11. PubMed
  • Boussiotis VA, Freeman GJ, Gray G, Gribben J, Nadler LM. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance. J Exp Med 1993; 178:1753-63. PubMed
  • Gimmi CD, Freeman GJ, Gribben JG, Gray G, Nadler LM. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci U S A 1993; 90:6586-90. PubMed
  • Baskar S, Ostrand-Rosenberg S, Nabavi N, Nadler LM, Freeman GJ, Glimcher LH. Constitutive expression of B7 restores immunogenicity of tumor cells expressing truncated major histocompatibility complex class II molecules. Proc Natl Acad Sci U S A 1993; 90:5687-90. PubMed
  • Freeman GJ, Gray GS, Gimmi CD, Lombard DB, Zhou LJ, White M, Fingeroth JD, Gribben JG, Nadler LM. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med 1991; 174:625-31. PubMed
  • Gimmi CD, Freeman GJ, Gribben JG, Sugita K, Freedman AS, Morimoto C, Nadler LM. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A 1991; 88:6575-9. PubMed
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