Photo of Arlene H. Sharpe,  MD, PhD

Arlene H. Sharpe, MD, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-6568
Fax: (617) 432-6570

Arlene H. Sharpe, MD, PhD

Harvard Medical School


  • George Fabyan Professor of Comparative Pathology, Microbiology and Immunobiology, Harvard Medical School
  • Vice Chair for Education, Pathology, Harvard Medical School
  • Co-Director, HITI, Harvard Medical School



  • Member, Center Scientific Council

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.


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  • Sage PT, Tan CL, Freeman GJ, Haigis M, Sharpe AH. Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep 2015; 12:163-71. 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
  • Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 2015; 16:188-96. PubMed
  • Godec J, Cowley GS, Barnitz RA, Root DE, Sharpe AH, Haining WN. Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation. Proc Natl Acad Sci U S A 2015; 112:512-7. PubMed
  • Sage PT, Sharpe AH. In Vitro Assay to Sensitively Measure TFR Suppressive Capacity and TFH Stimulation of B Cell Responses. Methods Mol Biol 2015; 1291:151-60. PubMed
  • Ron-Harel N, Sharpe AH, Haigis MC. Mitochondrial metabolism in T cell activation and senescence: a mini-review. Gerontology 2015; 61:131-8. PubMed
  • Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 2015. PubMed
  • Sage PT, Paterson AM, Lovitch SB, Sharpe AH. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 2014; 41:1026-39. PubMed
  • Sage PT, Alvarez D, Godec J, von Andrian UH, Sharpe AH. Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest 2014; 124:5191-204. PubMed
  • Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014; 515:577-81. PubMed
  • Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O'Mara L, Yang S, Konieczny BT, Sharpe AH, Freeman GJ, Rudensky AY, Ahmed R. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 2014; 211:1905-18. 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
  • 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
  • Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, Sharpe AH, Quintana FJ, Mathis D, Benoist C, Hafler DA, Kuchroo VK. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014; 40:569-81. 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
  • 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
  • Cooper ZA, Frederick DT, Juneja VR, Sullivan RJ, Lawrence DP, Piris A, Sharpe AH, Fisher DE, Flaherty KT, Wargo JA. BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology 2013; 2:e26615. 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
  • Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, Lovitch SB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013; 50:686-98. PubMed
  • Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol 2013; 14:152-61. PubMed
  • Maazi H, Singh AK, Speak AO, Lombardi V, Lam J, Khoo B, Inn KS, Sharpe AH, Jung JU, Akbari O. Lack of PD-L1 Expression by iNKT Cells Improves the Course of Influenza A Infection. PLoS ONE 2013; 8:e59599. PubMed
  • Sham CW, Chan AM, Kwong JM, Caprioli J, Nusinowitz S, Chen B, Lee JG, Gandhi NM, Francisco LM, Sharpe AH, Chen L, Braun J, Gordon LK. Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice. J Neuroophthalmol 2012; 32:227-37. PubMed
  • Silberman D, Bucknum A, Bartlett T, Composto G, Kozlowski M, Walker A, Werda A, Cua J, Sharpe AH, Somerville JE, Riggs JE. CD28 ligation increases macrophage suppression of T-cell proliferation. Cell Mol Immunol 2012; 9:341-9. PubMed
  • Hirahara K, Ghoreschi K, Yang XP, Takahashi H, Laurence A, Vahedi G, Sciumè G, Hall AO, Dupont CD, Francisco LM, Chen Q, Tanaka M, Kanno Y, Sun HW, Sharpe AH, Hunter CA, O'Shea JJ. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 2012; 36:1017-30. PubMed
  • Butte MJ, Lee SJ, Jesneck J, Keir ME, Haining WN, Sharpe AH. CD28 costimulation regulates genome-wide effects on alternative splicing. PLoS ONE 2012; 7:e40032. PubMed
  • Jin Y, Chauhan SK, Annan JE, Sage PT, Sharpe AH, Dana R. A novel function for programmed death ligand-1 regulation of angiogenesis. Am J Pathol 2011; 178:1922-9. 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
  • 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
  • Barber DL, Mayer-Barber KD, Feng CG, Sharpe AH, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 2011; 186:1598-607. PubMed
  • Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, Sharpe AH, Kuchroo VK. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 2011; 186:1338-42. PubMed
  • Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 2010; 116:2484-93. PubMed
  • Mueller SN, Vanguri VK, Ha SJ, West EE, Keir ME, Glickman JN, Sharpe AH, Ahmed R. PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J Clin Invest 2010; 120:2508-15. PubMed
  • Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236:219-42. 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
  • Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 2010; 11:535-42. PubMed
  • Paterson AM, Sharpe AH. Taming tissue-specific T cells: CTLA-4 reins in self-reactive T cells. Nat Immunol 2010; 11:109-11. 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
  • Ruffner MA, Kim SH, Bianco NR, Francisco LM, Sharpe AH, Robbins PD. B7-1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function. Eur J Immunol 2010; 39:3084-90. 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
  • Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 2009; 183:797-801. PubMed
  • Sharpe AH. Mechanisms of costimulation. Immunol Rev 2009; 229:5-11. PubMed
  • Verhagen J,Gabrysova L,Minaee S,Sabatos CA,Anderson G,Sharpe AH,Wraith DC. Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease. Proc Natl Acad Sci U S A 2009; 106:3306-11. 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
  • Bauquet AT,Jin H,Paterson AM,Mitsdoerffer M,Ho IC,Sharpe AH,Kuchroo VK. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 2008; 10:167-75. PubMed
  • Schmidt EM,Wang CJ,Ryan GA,Clough LE,Qureshi OS,Goodall M,Abbas AK,Sharpe AH,Sansom DM,Walker LS. Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J Immunol 2008; 182:274-82. 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
  • Gotsman I,Sharpe AH,Lichtman AH. T-cell costimulation and coinhibition in atherosclerosis. Circ Res 2008; 103:1220-31. PubMed
  • Taylor PA,Ehrhardt MJ,Lees CJ,Panoskaltsis-Mortari A,Krieg AM,Sharpe AH,Murphy WJ,Serody JS,Hemmi H,Akira S,Levy RB,Blazar BR. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 2008; 112:3508-16. PubMed
  • Duan B,Niu H,Xu Z,Sharpe AH,Croker BP,Sobel ES,Morel L. Intrafollicular location of marginal zone/CD1d(hi) B cells is associated with autoimmune pathology in a mouse model of lupus. Lab Invest 2008; 88:1008-20. PubMed
  • Lucas JA,Menke J,Rabacal WA,Schoen FJ,Sharpe AH,Kelley VR. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 2008; 181:2513-21. 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
  • 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
  • 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
  • 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
  • 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; 117:2974-82. 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
  • 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; 104:13756-61. PubMed
  • 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; 101:248-57. 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
  • Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 2007; 19:309-14. 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