Control of Regulatory T Cells by Co-signal Molecules

  • James Badger Wing
  • Christopher Tay
  • Shimon SakaguchiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1189)


Foxp3-expressing regulatory T cells (Tregs) perform a vital function in the maintenance of immune homeostasis. A large part of Treg suppressive function is derived from their ability to control and restrict the availability of co-signal molecules to other T cells. However, Tregs themselves also depend on many of the same co-signals for their own homeostasis, making this a complex system of feedback. In this chapter, we discuss the critical role of co-signaling in Treg cell biology.


Tregs CTLA-4 PD-1 CD28 OX40 GITR CD27 CD30 TIGIT DR3 TNFR2 ICOS Tim-3 


  1. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. CrossRefPubMedGoogle Scholar
  2. Adams AB, Ford ML, Larsen CP (2016) Costimulation blockade in autoimmunity and transplantation: the CD28 pathway. J Immunol 197(6):2045–2050. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8(9):1024–1032. CrossRefPubMedGoogle Scholar
  4. Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184(2):387–396CrossRefGoogle Scholar
  6. Bachmann MF, Kohler G, Ecabert B, Mak TW, Kopf M (1999) Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J Immunol 163(3):1128–1131PubMedGoogle Scholar
  7. Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM (2003) Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J Immunol 170(2):711–718CrossRefGoogle Scholar
  8. Bettini M, Szymczak-Workman AL, Forbes K, Castellaw AH, Selby M, Pan X, Drake CG, Korman AJ, Vignali DA (2011) Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3. J Immunol 187(7):3493–3498. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Beyersdorf N, Hanke T, Kerkau T, Hunig T (2006) CD28 superagonists put a break on autoimmunity by preferentially activating CD4+CD25+ regulatory T cells. Autoimmun Rev 5(1):40–45. CrossRefPubMedGoogle Scholar
  10. Blank C, Brown I, Marks R, Nishimura H, Honjo T, Gajewski TF (2003) Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J Immunol 171(9):4574–4581CrossRefGoogle Scholar
  11. Bretscher P, Cohn M (1970) A theory of self-nonself discrimination. Science 169(3950):1042–1049CrossRefGoogle Scholar
  12. Bullock TN (2017) Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer. Curr Opin Immunol 45:82–88. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Burmeister Y, Lischke T, Dahler AC, Mages HW, Lam KP, Coyle AJ, Kroczek RA, Hutloff A (2008) ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol 180(2):774–782CrossRefGoogle Scholar
  14. Burzyn D, Benoist C, Mathis D (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14(10):1007–1013. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Busse M, Krech M, Meyer-Bahlburg A, Hennig C, Hansen G (2012) ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance. J Immunol 189(4):1975–1982. CrossRefPubMedGoogle Scholar
  16. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27(1):111–122. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Callahan MK, Postow MA, Wolchok JD (2014) CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front Oncol 4:385. CrossRefPubMedGoogle Scholar
  18. Chen AI, McAdam AJ, Buhlmann JE, Scott S, Lupher ML Jr, Greenfield EA, Baum PR, Fanslow WC, Calderhead DM, Freeman GJ, Sharpe AH (1999) Ox40-ligand has a critical costimulatory role in dendritic cell: T cell interactions. Immunity 11(6):689–698CrossRefGoogle Scholar
  19. Chen X, Baumel M, Mannel DN, Howard OM, Oppenheim JJ (2007) Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol 179(1):154–161CrossRefGoogle Scholar
  20. Chen X, Wu X, Zhou Q, Howard OM, Netea MG, Oppenheim JJ (2013) TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J Immunol 190(3):1076–1084. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M (2012) Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 13(9):832–842. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Claus C, Riether C, Schurch C, Matter MS, Hilmenyuk T, Ochsenbein AF (2012) CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res 72(14):3664–3676. CrossRefPubMedGoogle Scholar
  23. Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G, Xiao Y, Neves JF, Fonseca-Pereira D, Jacobs H, Pennington DJ, Silva-Santos B, Borst J (2013) Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J Exp Med 210(4):715–728. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Croft M (2014) The TNF family in T cell differentiation and function – unanswered questions and future directions. Semin Immunol 26(3):183–190. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP (2011) Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 6(4):e19499. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Dai Z, Li Q, Wang Y, Gao G, Diggs LS, Tellides G, Lakkis FG (2004) CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism. J Clin Invest 113(2):310–317. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Dhainaut M, Coquerelle C, Uzureau S, Denoeud J, Acolty V, Oldenhove G, Galuppo A, Sparwasser T, Thielemans K, Pays E, Yagita H, Borst J, Moser M (2015) Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells. EMBO J 34(10):1336–1348. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ellestad KK, Thangavelu G, Ewen CL, Boon L, Anderson CC (2014) PD-1 is not required for natural or peripherally induced regulatory T cells: severe autoimmunity despite normal production of regulatory T cells. Eur J Immunol 44(12):3560–3572. CrossRefPubMedGoogle Scholar
  29. Elpek KG, Yolcu ES, Franke DD, Lacelle C, Schabowsky RH, Shirwan H (2007) Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling. J Immunol 179(11):7295–7304CrossRefGoogle Scholar
  30. Ephrem A, Epstein AL, Stephens GL, Thornton AM, Glass D, Shevach EM (2013) Modulation of Treg cells/T effector function by GITR signaling is context-dependent. Eur J Immunol 43(9):2421–2429. CrossRefPubMedGoogle Scholar
  31. Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, Erickson J, Leonard JP (2002) Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 9(2):133–145. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg FG, Higgins JP, Negrin RS, Fathman CG, Strober S (2005) Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105(5):2220–2226. CrossRefPubMedGoogle Scholar
  33. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034CrossRefGoogle Scholar
  35. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 203(10):2223–2227. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Fuhrman CA, Yeh WI, Seay HR, Saikumar Lakshmi P, Chopra G, Zhang L, Perry DJ, McClymont SA, Yadav M, Lopez MC, Baker HV, Zhang Y, Li Y, Whitley M, von Schack D, Atkinson MA, Bluestone JA, Brusko TM (2015) Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol 195(1):145–155. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gautron AS, Dominguez-Villar M, de Marcken M, Hafler DA (2014) Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J Immunol 44(9):2703–2711. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS (2015) Regulatory T-cells in autoimmune diseases: challenges, controversies and--yet--unanswered questions. Autoimmun Rev 14(2):105–116. CrossRefPubMedGoogle Scholar
  39. Griseri T, Asquith M, Thompson C, Powrie F (2010) OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med 207(4):699–709. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC, Goldberg MV, Pardoll DM, Drake CG (2007) LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 117(11):3383–3392. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Guo F, Iclozan C, Suh WK, Anasetti C, Yu XZ (2008) CD28 controls differentiation of regulatory T cells from naive CD4 T cells. J Immunol 181(4):2285–2291CrossRefGoogle Scholar
  42. Gupta S, Thornley TB, Gao W, Larocca R, Turka LA, Kuchroo VK, Strom TB (2012) Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs. J Clin Invest 122(7):2395–2404. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Hannier S, Tournier M, Bismuth G, Triebel F (1998) CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol 161(8):4058–4065PubMedGoogle Scholar
  44. Herman AE, Freeman GJ, Mathis D, Benoist C (2004) CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199(11):1479–1489. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Hombach AA, Kofler D, Hombach A, Rappl G, Abken H (2007) Effective proliferation of human regulatory T cells requires a strong costimulatory CD28 signal that cannot be substituted by IL-2. J Immunol 179(11):7924–7931CrossRefGoogle Scholar
  46. Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA (2004) Role of LAG-3 in regulatory T cells. Immunity 21(4):503–513. CrossRefGoogle Scholar
  47. Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F (1995) CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 25(9):2718–2721. CrossRefPubMedGoogle Scholar
  48. Iwai Y, Hamanishi J, Chamoto K, Honjo T (2017) Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 24(1):26. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, Sharpe AH, Kuchroo VK (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186(3):1338–1342. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 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 (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40(4):569–581. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY (2012) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482(7385):395–399. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Karunarathne DS, Horne-Debets JM, Huang JX, Faleiro R, Leow CY, Amante F, Watkins TS, Miles JJ, Dwyer PJ, Stacey KJ, Yarski M, Poh CM, Lee JS, Cooper MA, Rénia L, Richard D, McCarthy JS, Sharpe AH, Wykes MN (2016) Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4(+) T cell immunity. Immunity 45(2):333–345. CrossRefPubMedGoogle Scholar
  53. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191–197. CrossRefPubMedGoogle Scholar
  54. Kim BS, Nishikii H, Baker J, Pierini A, Schneidawind D, Pan Y, Beilhack A, Park CG, Negrin RS (2015) Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood 126(4):546–557. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Kinnear G, Wood KJ, Fallah-Arani F, Jones ND (2013) A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen. J Immunol 191(3):1465–1475. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Klocke K, Sakaguchi S, Holmdahl R, Wing K (2016) Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc Natl Acad Sci U S A 113(17):E2383–E2392. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, Shimizu J, Nomura T, Chiba T, Sakaguchi S (2005) Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 202(7):885–891. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Kocak E, Lute K, Chang X, May KF Jr, Exten KR, Zhang H, Abdessalam SF, Lehman AM, Jarjoura D, Zheng P, Liu Y (2006) Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res 66(14):7276–7284. CrossRefPubMedGoogle Scholar
  59. Koguchi K, Anderson DE, Yang L, O’Connor KC, Kuchroo VK, Hafler DA (2006) Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med 203(6):1413–1418. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Kong K-F, Fu G, Zhang Y, Yokosuka T, Casas J, Canonigo-Balancio AJ, Becart S, Kim G, Yates JR, Kronenberg M, Saito T, Gascoigne NRJ, Altman A (2014) Protein kinase C-η controls CTLA-4-mediated regulatory T cell function. Nat Immunol 15(5):465–472. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Kornete M, Sgouroudis E, Piccirillo CA (2012) ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 188(3):1064–1074. CrossRefPubMedGoogle Scholar
  62. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345(6204):1623–1627. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, Smyth MJ, Kuchroo VK, Anderson AC (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125(11):4053–4062. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kwon BS, Hurtado JC, Lee ZH, Kwack KB, Seo SK, Choi BK, Koller BH, Wolisi G, Broxmeyer HE, Vinay DS (2002) Immune responses in 4-1BB (CD137)-deficient mice. J Immunol 168(11):5483–5490CrossRefGoogle Scholar
  65. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Li A, Jacks T (2017) Driving Rel-iant Tregs toward an identity crisis. Immunity 47(3):391–393. CrossRefPubMedGoogle Scholar
  67. Li M, Xia P, Du Y, Liu S, Huang G, Chen J, Zhang H, Hou N, Cheng X, Zhou L, Li P, Yang X, Fan Z (2014) T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J Biol Chem 289(25):17647–17657. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Liao G, Nayak S, Regueiro JR, Berger SB, Detre C, Romero X, de Waal Malefyt R, Chatila TA, Herzog RW, Terhorst C (2010) GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells. Int Immunol 22(4):259–270. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Lin CH, Hunig T (2003) Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 33(3):626–638. CrossRefPubMedGoogle Scholar
  70. Lio CW, Hsieh CS (2008) A two-step process for thymic regulatory T cell development. Immunity 28(1):100–111. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Liu X, Gao JX, Wen J, Yin L, Li O, Zuo T, Gajewski TF, Fu YX, Zheng P, Liu Y (2003) B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism. J Exp Med 197(12):1721–1730. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Lohr J, Knoechel B, Jiang S, Sharpe AH, Abbas AK (2003) The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat Immunol 4(7):664–669. CrossRefPubMedGoogle Scholar
  73. Loke P, Allison JP (2003) PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A 100(9):5336–5341. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904. CrossRefPubMedGoogle Scholar
  75. Lowther DE, Goods BA, Lucca LE, Lerner BA, Raddassi K, van Dijk D, Hernandez AL, Duan X, Gunel M, Coric V, Krishnaswamy S, Love JC, Hafler DA (2016) PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1(5).
  76. Maerten P, Kwon BS, Shen C, De Hertogh G, Cadot P, Bullens DM, Overbergh L, Mathieu C, Van Assche G, Geboes K, Rutgeerts P, Ceuppens JL (2006) Involvement of 4-1BB (CD137)-4-1BBligand interaction in the modulation of CD4 T cell-mediated inflammatory colitis. Clin Exp Immunol 143(2):228–236. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, Schenkel JM, Boomer JS, Green JM, Yagita H, Chi H, Ka H, Ma F (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15(5):473–481. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Mandelbrot DA, McAdam AJ, Sharpe AH (1999) 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 189(2):435–440CrossRefGoogle Scholar
  79. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16(2):311–323CrossRefGoogle Scholar
  80. Meagher C, Tang Q, Fife BT, Bour-Jordan H, Wu J, Pardoux C, Bi M, Melli K, Bluestone JA (2008) Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice. J Immunol 180(12):7793–7803CrossRefGoogle Scholar
  81. Messal N, Serriari NE, Pastor S, Nunès JA, Olive D (2011) PD-L2 is expressed on activated human T cells and regulates their function. Mol Immunol 48(15-16):2214–2219. CrossRefPubMedGoogle Scholar
  82. Miyamoto K, Kingsley CI, Zhang X, Jabs C, Izikson L, Sobel RA, Weiner HL, Kuchroo VK, Sharpe AH (2005) The ICOS molecule plays a crucial role in the development of mucosal tolerance. J Immunol 175(11):7341–7347CrossRefGoogle Scholar
  83. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541. CrossRefPubMedGoogle Scholar
  84. Murata K, Nose M, Ndhlovu LC, Sato T, Sugamura K, Ishii N (2002) Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol 169(8):4628–4636CrossRefGoogle Scholar
  85. Nie H, Zheng Y, Li R, Zhang J (2016) Reply to Suppressive activity of human regulatory T cells is maintained in the presence of TNF. Nat Med 22(1):18–19. CrossRefPubMedGoogle Scholar
  86. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 8(5):773–780CrossRefGoogle Scholar
  87. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151CrossRefGoogle Scholar
  88. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322. CrossRefGoogle Scholar
  89. Nishizuka Y, Sakakura T (1969) Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166(3906):753–755CrossRefGoogle Scholar
  90. Nocentini G, Riccardi C (2005) GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 35(4):1016–1022. CrossRefPubMedGoogle Scholar
  91. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, Yu XZ, Dong C (2006) T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J 25(11):2623–2633. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 181(7):4832–4839CrossRefGoogle Scholar
  93. Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38(3):414–423. CrossRefPubMedGoogle Scholar
  94. Okubo Y, Mera T, Wang L, Faustman DL (2013) Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci Rep 3:3153. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008) Foxp3(+) natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A 105(29):10113–10118. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Piconese S, Valzasina B, Colombo MP (2008) OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205(4):825–839. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Piconese S, Gri G, Tripodo C, Musio S, Gorzanelli A, Frossi B, Pedotti R, Pucillo CE, Colombo MP (2009) Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood 114(13):2639–2648. CrossRefPubMedGoogle Scholar
  99. Ramsdell F, Ziegler SF (2014) FOXP3 and scurfy: how it all began. Nat Rev Immunol 14(5):343–349. CrossRefPubMedGoogle Scholar
  100. Redmond WL, Weinberg AD (2007) Targeting OX40 and OX40L for the treatment of autoimmunity and cancer. Crit Rev Immunol 27(5):415–436CrossRefGoogle Scholar
  101. Ronchetti S, Zollo O, Bruscoli S, Agostini M, Bianchini R, Nocentini G, Ayroldi E, Riccardi C (2004) GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 34(3):613–622. CrossRefPubMedGoogle Scholar
  102. Rui Y, Honjo T, Chikuma S (2013) Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc Natl Acad Sci U S A 110(40):16073–16078. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Sage PT, Francisco LM, Carman CV, Sharpe AH (2013) The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol 14(2):152–161. CrossRefPubMedGoogle Scholar
  104. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164PubMedGoogle Scholar
  105. Sakuishi K, Ngiow SF, Sullivan JM, Teng MW, Kuchroo VK, Smyth MJ, Anderson AC (2013) TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology 2(4):e23849. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12(4):431–440CrossRefGoogle Scholar
  107. Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I (2015) Agonists of Co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 42(4):640–655. CrossRefPubMedGoogle Scholar
  108. Schoenbrunn A, Frentsch M, Kohler S, Keye J, Dooms H, Moewes B, Dong J, Loddenkemper C, Sieper J, Wu P, Romagnani C, Matzmohr N, Thiel A (2012) A converse 4-1BB and CD40 ligand expression pattern delineates activated regulatory T cells (Treg) and conventional T cells enabling direct isolation of alloantigen-reactive natural Foxp3+ Treg. J Immunol 189(12):5985–5994. CrossRefPubMedGoogle Scholar
  109. Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L, Malek TR, Levy RB, Podack ER (2010) Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J Clin Invest 120(10):3629–3640. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schaffer AA, Gruning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LS, Sansom DM, Grimbacher B (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20(12):1410–1416. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Sega EI, Leveson-Gower DB, Florek M, Schneidawind D, Luong RH, Negrin RS (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9(1):e86551. CrossRefPubMedPubMedCentralGoogle Scholar
  112. Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, Shi H, Munn DH (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38(5):998–1012. CrossRefPubMedPubMedCentralGoogle Scholar
  113. Sharpe AH, Freeman GJ (2002) The B7-CD28 superfamily. Nat Rev Immunol 2(2):116–126. CrossRefGoogle Scholar
  114. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3(2):135–142. CrossRefGoogle Scholar
  115. Shin T, Kennedy G, Gorski K, Tsuchiya H, Koseki H, Azuma M, Yagita H, Chen L, Powell J, Pardoll D, Housseau F (2003) Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J Exp Med 198(1):31–38. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Sidorenko SP, Clark EA (2003) The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol 4(1):19–24. CrossRefPubMedGoogle Scholar
  117. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695–1710. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini R, Riccardi C (2002) GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. Cell Death Differ 9(12):1382–1384. CrossRefPubMedGoogle Scholar
  119. Stephen TL, Payne KK, Chaurio RA, Allegrezza MJ, Zhu H, Perez-Sanz J, Perales-Puchalt A, Nguyen JM, Vara-Ailor AE, Eruslanov EB, Borowsky ME, Zhang R, Laufer TM, Conejo-Garcia JR (2017) SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 46(1):51–64. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, Collins M, Shevach EM (2004) Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173(8):5008–5020CrossRefGoogle Scholar
  121. Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, Sakaguchi S (2006) Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 18(8):1197–1209. CrossRefPubMedGoogle Scholar
  122. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355(10):1018–1028. CrossRefPubMedGoogle Scholar
  123. Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6(2):152–162. CrossRefPubMedGoogle Scholar
  124. Tai X, Van Laethem F, Sharpe AH, Singer A (2007) 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 104(34):13756–13761. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Takeda I, Ine S, Killeen N, Ndhlovu LC, Murata K, Satomi S, Sugamura K, Ishii N (2004) Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 172(6):3580–3589CrossRefGoogle Scholar
  126. Tanaka A, Sakaguchi S (2017) Regulatory T cells in cancer immunotherapy. Cell Res 27(1):109–118. CrossRefPubMedGoogle Scholar
  127. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171(7):3348–3352CrossRefGoogle Scholar
  128. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547CrossRefGoogle Scholar
  129. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H (2001) B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 193(7):839–846CrossRefGoogle Scholar
  130. Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP (2005) Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105(7):2845–2851. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Vasanthakumar A, Liao Y, Teh P, Pascutti MF, Oja AE, Garnham AL, Gloury R, Tempany JC, Sidwell T, Cuadrado E, Tuijnenburg P, Kuijpers TW, Lalaoui N, Mielke LA, Bryant VL, Hodgkin PD, Silke J, Smyth GK, Nolte MA, Shi W, Kallies A (2017) The TNF receptor superfamily-NF-kappaB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues. Cell Rep 20(12):2906–2920. CrossRefPubMedGoogle Scholar
  132. Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110(7):2501–2510. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Walker LSK, Sansom DM (2015) Confusing signals: recent progress in CTLA-4 biology. Trends Immunol:1–8. CrossRefGoogle Scholar
  134. Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T (2005) Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci U S A 102(33):11823–11828. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Webb GJ, Hirschfield GM, Lane PJ (2016) OX40, OX40L and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol 50(3):312–332. CrossRefPubMedGoogle Scholar
  137. Wikenheiser DJ, Stumhofer JS (2016) ICOS co-stimulation: friend or foe? Front Immunol 7:304. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20. CrossRefPubMedGoogle Scholar
  139. Wing JB, Sakaguchi S (2012) Multiple treg suppressive modules and their adaptability. Front Immunol 3:178. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. CrossRefGoogle Scholar
  141. Wing K, Yamaguchi T, Sakaguchi S (2011) Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol 32(9):428–433. CrossRefPubMedGoogle Scholar
  142. Wing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, Kidani Y, Matsuda K, Inoue T, Kurosaki T, Crotty S, Coban C, Ohkura N, Sakaguchi S (2017) A distinct subpopulation of CD25- T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci U S A 114(31):E6400–E6409. CrossRefPubMedPubMedCentralGoogle Scholar
  143. Workman CJ, Dugger KJ, Vignali DA (2002) Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 169(10):5392–5395CrossRefGoogle Scholar
  144. Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, Bishop DK, Turka LA, Li XC (2012) New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol 188(2):892–901. CrossRefPubMedGoogle Scholar
  145. Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, Du X, Tang L, He F (2014) LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 74(13):3418–3428. CrossRefPubMedGoogle Scholar
  146. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169(10):5538–5545CrossRefGoogle Scholar
  147. Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, Tom I, Ivelja S, Refino CJ, Clark H, Eaton D, Grogan JL (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10(1):48–57. CrossRefPubMedPubMedCentralGoogle Scholar
  148. Zeiser R, Nguyen VH, Hou JZ, Beilhack A, Zambricki E, Buess M, Contag CH, Negrin RS (2007) Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease. Blood 109(5):2225–2233. CrossRefPubMedPubMedCentralGoogle Scholar
  149. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20(3):337–347CrossRefGoogle Scholar
  150. Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA (2013) An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 123(2):580–593. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Zhang B, Chikuma S, Hori S, Fagarasan S, Honjo T (2016) Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A 113(30):8490–8495. CrossRefPubMedPubMedCentralGoogle Scholar
  152. Zhang Q, Chikina M, Szymczak-Workman AL, Horne W, Kolls JK, Vignali KM, Normolle D, Bettini M, Workman CJ, Vignali DAA (2017) LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci Immunol 2(9). CrossRefGoogle Scholar
  153. Zheng G, Wang B, Chen A (2004) The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells. J Immunol 173(4):2428–2434CrossRefGoogle Scholar
  154. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL (2007) PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 37(9):2405–2410. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • James Badger Wing
    • 1
  • Christopher Tay
    • 1
  • Shimon Sakaguchi
    • 1
    • 2
    Email author
  1. 1.Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center (IFReC)Osaka UniversityOsakaJapan
  2. 2.Department of Experimental Pathology, Institute for Frontier Medical SciencesKyoto UniversityKyotoJapan

Personalised recommendations