DF/HCC Program Affiliation

Cancer Genetics
Cancer Immunology

Research Abstract

Dr. Sharpe's research is focused on understanding the role of costimulatory molecules in T cell activation in vivo. Learning how to manipulate costimulatory pathways may provide new therapeutic approaches for augmenting immunity to microbes and tumor antigens, as well as for inhibiting immune responses to prevent graft rejection and treat autoimmune diseases. The approach that her laboratory has taken is to focus on the obligatory in vivo functions of costimulatory molecules by using targeted gene disruption to generate mouse strains lacking T cell costimulatory molecules. Analysis of the key costimulatory pathway involving B7 costimulatory molecules and their receptors, CD28 and CTLA-4, has been her major focus. Her laboratory is investigating the role of B7-1 and B7-2 in T cell activation, T cell tolerance, and autoimmune responses. By examining what factors elicit residual immune responses in mice lacking both B7 costimulators, her laboratory is also examining the role of additional costimulatory pathways in T cell activation. The laboratory is studying interactions between costimulatory pathways and the hierarchy of costimulatory pathways throughout the generation and analysis of mice lacking other costimulatory molecules (including CD48, OX40 ligand, CD40 ligand and SLAM). A second project focuses on analyzing the critical negative regulatory role of CTLA-4 in T cell activation and tolerance. The third project is directed at defining the molecular basis for the highly regulated expression of B7 costimulatory molecules. Because genetic mapping studies have identified the chromosomal regions containing CD28/CTLA-4 and B7/B7-2 loci as important for the development of IDDM and EAE, the laboratory is also examining whether polymorphisms within these genes lead to altered expression or protein function in autoimmune prone mouse strains, thereby contributing the pathogenesis of autoimmunity.

Publications

• Chang TT, Jabs C, Sobel RA, Kuchroo VK, Sharpe AH.Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis.J Exp Med 1999 Sep 6;190(5):733-40.
  10477557
• 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 Apr 15;180(8):5448-56.
  18390727
• 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 Mar 17;205(3):543-55.
  18332181
• Keir ME, Butte MJ, Freeman GJ, Sharpe AH.PD-1 and Its Ligands in Tolerance and Immunity.Annu Rev Immunol 2008 Apr;26:677-704.
  18173375
• Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ.TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine
  18082433
• 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 Oct 15;179(8):5064-70.
  17911591
• 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 Sep 25;104(
  17878315
• Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH.Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice.J Clin Invest 2007 Oct;117(10):2974-82.
  17853943
• 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 Sep 15;179(6):3672-9.
  17785803
• Tai X, Van Laethem F, Sharpe AH, Singer A.Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation.Proc Natl Acad Sci U S A 2007 Aug 21;104(34):13756-61.
  17702861
• 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 Jul;27(1):111-22.
  17629517
• Love VA, Grabie N, Duramad P, Stavrakis G, Sharpe A, Lichtman A.CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes.Circ Res 2007 Aug 3;101(3):248-57.
  17569889
• Keir ME, Francisco LM, Sharpe AH.PD-1 and its ligands in T-cell immunity.Curr Opin Immunol 2007 Jun;19(3):309-14.
  17433872
• 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 Apr 17;203(4):883-95.
  16606670
• 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 2006 Feb 9;439(7077):682-7.
  16382236
• 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 2006 Jan;36(1):58-64.
  16358363
• Keir ME, Sharpe AH.The B7/CD28 costimulatory family in autoimmunity.Immunol Rev 2005 Apr;204:128-43.
  15790355
• 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 eng
  15618467
• 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 Jul 20;101
  15249675
• Vijayakrishnan L, Slavik JM, Illés Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK.An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells
  15142525
• 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 May 3;199(9):1255-64.
  15123745
• Martin-Orozco N, Chen Z, Poirot L, Hyatt E, Chen A, Kanagawa O, Sharpe A, Mathis D, Benoist C.Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand.J Immunol 2003 Dec 15;171(12):6954-60.
  14662903
• 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 Nov;33(11):3117-26.
  14579280
• 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 Oct;33(10):2706-16.
  14515254
• 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 Jul;112(2):234-43.
  12865411
• Ekkens MJ, Liu Z, Liu Q, Whitmire J, Xiao S, Foster A, Pesce J, VanNoy J, Sharpe AH, Urban JF, Gause WC.The role of OX40 ligand interactions in the development of the Th2 response to the gastrointestinal nematode parasite Heligmosomoides polygyrus.J Immun
  12496423
• Schneider H, Mandelbrot DA, Greenwald RJ, Ng F, Lechler R, Sharpe AH, Rudd CE.Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from
  12244135
• Jabs C, Greve B, Chang TT, Sobel RA, Sharpe AH, Kuchroo VK.Genetic background determines the requirement for B7 costimulation in induction of autoimmunity.Eur J Immunol 2002 Sep;32(9):2687-97.
  12207354
• Freeman GJ, Sharpe AH, Kuchroo VK.Protect the killer: CTLs need defenses against the tumor.Nat Med 2002 Aug;8(8):787-9.
  12152031
• 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 Sep;8(9):1024
  12145647
• Brown JA, Greenwald RJ, Scott S, Schweitzer AN, Satoskar AR, Chung C, Schopf LR, van der Woude D, Sypek JP, Sharpe AH.T helper differentiation in resistant and susceptible B7-deficient mice infected with Leishmania major.Eur J Immunol 2002 Jun;32(6):1764-
  12115660
• Ekkens MJ, Liu Z, Liu Q, Foster A, Whitmire J, Pesce J, Sharpe AH, Urban JF, Gause WC.Memory Th2 effector cells can develop in the absence of B7-1/B7-2, CD28 interactions, and effector Th cells after priming with an intestinal nematode parasite.J Immunol
  12055251
• Greenwald RJ, Latchman YE, Sharpe AH.Negative co-receptors on lymphocytes.Curr Opin Immunol 2002 Jun;14(3):391-6.
  11973140
• Sharpe AH, Freeman GJ.The B7-CD28 superfamily.Nat Rev Immunol 2002 Feb;2(2):116-26.
  11910893
• Chang TT, Kuchroo VK, Sharpe AH.Role of the B7-CD28/CTLA-4 pathway in autoimmune disease.Curr Dir Autoimmun 2002;5:113-30.
  11826754
• Greenwald RJ, Oosterwegel MA, van der Woude D, Kubal A, Mandelbrot DA, Boussiotis VA, Sharpe AH.CTLA-4 regulates cell cycle progression during a primary immune response.Eur J Immunol 2002 Feb;32(2):366-73.
  11807776
• Greenwald RJ, McAdam AJ, Van der Woude D, Satoskar AR, Sharpe AH.Cutting edge: inducible costimulator protein regulates both Th1 and Th2 responses to cutaneous leishmaniasis.J Immunol 2002 Feb 1;168(3):991-5.
  11801630
• Mandelbrot DA, Kishimoto K, Auchincloss H, Sharpe AH, Sayegh MH.Rejection of mouse cardiac allografts by costimulation in trans.J Immunol 2001 Aug 1;167(3):1174-8.
  11466331
• Witke W, Sutherland JD, Sharpe A, Arai M, Kwiatkowski DJ.Profilin I is essential for cell survival and cell division in early mouse development.Proc Natl Acad Sci U S A 2001 Mar 27;98(7):3832-6.
  11274401
• Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB.Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-
  10891488
• Anderson DE, Sharpe AH, Hafler DA.The B7-CD28/CTLA-4 costimulatory pathways in autoimmune disease of the central nervous system.Curr Opin Immunol 1999 Dec;11(6):677-83.
  10631554
• Humphries DE, Wong GW, Friend DS, Gurish MF, Qiu WT, Huang C, Sharpe AH, Stevens RL.Heparin is essential for the storage of specific granule proteases in mast cells.Nature 1999 Aug 19;400(6746):769-72.
  10466726
• Oosterwegel MA, Mandelbrot DA, Boyd SD, Lorsbach RB, Jarrett DY, Abbas AK, Sharpe AH.The role of CTLA-4 in regulating Th2 differentiation.J Immunol 1999 Sep 1;163(5):2634-9.
  10453003
• Khattri R, Auger JA, Griffin MD, Sharpe AH, Bluestone JA.Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses.J Immunol 1999 May 15;162(10):5784-91.
  10229811
• Greenwald RJ, Urban JF, Ekkens MJ, Chen S, Nguyen D, Fang H, Finkelman FD, Sharpe AH, Gause WC.B7-2 is required for the progression but not the initiation of the type 2 immune response to a gastrointestinal nematode parasite.J Immunol 1999 Apr 1;162(7):41
  10201938
• Hernandez HJ, Sharpe AH, Stadecker MJ.Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation.J Immunol 1999 Mar 1;162(5):2884-9.
  10072537
• González-Cabrero J, Wise CJ, Latchman Y, Freeman GJ, Sharpe AH, Reiser H.CD48-deficient mice have a pronounced defect in CD4(+) T cell activation.Proc Natl Acad Sci U S A 1999 Feb 2;96(3):1019-23.
  9927686
• Mandelbrot DA, McAdam AJ, Sharpe AH.B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).J Exp Med 1999 Jan 18;189(2):435-40.
  9892625
• Rauschmayr-Kopp T, Williams IR, Borriello F, Sharpe AH, Kupper TS.Distinct roles for B7 costimulation in contact hypersensitivity and humoral immune responses to epicutaneous antigen.Eur J Immunol 1998 Dec;28(12):4221-7.
  9862359
• La Motte RN, Sharpe AH, Bluestone JA, Mokyr MB.Importance of B7-1-expressing host antigen-presenting cells for the eradication of B7-2 transfected P815 tumor cells.J Immunol 1998 Dec 15;161(12):6552-8.
  9862681
• Schweitzer AN, Sharpe AH.Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production.J Immunol 1998 Se
  9743334
• Van Parijs L, Sethna MP, Schweitzer AN, Borriello F, Sharpe AH, Abbas AK.Functional consequences of dysregulated B7-1 (CD80) and B7-2 (CD86) expression in B or T lymphocytes of transgenic mice.J Immunol 1997 Dec 1;159(11):5336-44.
  9548473
• Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH.CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.J Immunol 1997 Jun 1;158(11):5091-4.
  9164923
• 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 Mar;6(3):303-13.
  9075931
• Lynch WP, Snyder EY, Qualtiere L, Portis JL, Sharpe AH.Late virus replication events in microglia are required for neurovirulent retrovirus-induced spongiform neurodegeneration: evidence from neural progenitor-derived chimeric mouse brains.J Virol 1996 De
  8971019
• Tivol EA, Schweitzer AN, Sharpe AH.Costimulation and autoimmunity.Curr Opin Immunol 1996 Dec;8(6):822-30.
  8994862
• Blazar BR, Sharpe AH, Taylor PA, Panoskaltsis-Mortari A, Gray GS, Korngold R, Vallera DA.Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8
  8871619
• Borriello F, Oliveros J, Freeman GJ, Nadler LM, Sharpe AH.Differential expression of alternate mB7-2 transcripts.J Immunol 1995 Dec 15;155(12):5490-7.
  7499829
• Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ.Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3.Science 1995 Nov 3;270(5237):794-7.
  7481767
• Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH.Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.Immunity 1995 Nov;3(5):541-7.
  7584144
• Sharpe AH.Analysis of lymphocyte costimulation in vivo using transgenic and 'knockout' mice.Curr Opin Immunol 1995 Jun;7(3):389-95.
  7546405
• Prabhu Das MR, Zamvil SS, Borriello F, Weiner HL, Sharpe AH, Kuchroo VK.Reciprocal expression of co-stimulatory molecules, B7-1 and B7-2, on murine T cells following activation.Eur J Immunol 1995 Jan;25(1):207-11.
  7531145