Skip to main content

Advertisement

SpringerLink
Log in

Foxp3 expression in T regulatory cells and other cell lineages

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Forkhead box P3 (Foxp3) is an important transcription factor that belongs to the forkhead/winged-helix family of transcriptional regulators. Foxp3 has been extensively studied over the past 13 years as a master regulator of transcription in a specific T-cell type, CD4+ regulatory T cells (Treg), both in humans and in mice. Compelling data characterize Foxp3 as critically important and necessary for the development and the differentiation of Treg. It has been considered initially as the only specific marker for Treg. However, recent work has proposed that Foxp3 can be expressed by other types of lymphoid cells or myeloid cells and also by some non-hematopoietic cells such as epithelial cells. It remains controversial about the expression of Foxp3 in cells other than Treg, but understanding the potential expression and function of this master regulator in different cell subsets could have a wide range of implications for immune tolerance and several pathologies including autoimmune disorders and immune responses to cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BM:

Bone marrow

BRCA1:

Breast cancer 1, early onset

CD:

Cluster of differentiation

CTLA4:

Cytotoxic T-lymphocyte antigen-4

DC:

Dendritic cells

DEREG:

Depletion of regulatory T cells

DNA:

Deoxyribonucleic acid

DT:

Diphtheria toxin

EAE:

Experimental autoimmune encephalomyelitis

FOX:

Forkhead box

GITR:

Glucocorticoid-induced tumor necrosis factor receptor family related gene

HAT:

Histone/protein acetyltransferases

HER:

Human epidermal growth factor receptor

IL:

Interleukin

IL2R:

Interleukin 2 receptor

NK:

Natural killer

iNKT:

Invariant natural killer T cells

IPEX:

Immune dysregulation, polyendocrinopathy, entheropathy, X-linked

IRF:

Interferon regulatory factor

PBMC:

Peripheral blood mononuclear cells

Rag:

Recombination-activating genes

RNA:

Ribonucleic acid

ROR:

Retinoid-related orphan receptor

SATB:

Special AT-rich sequence binding protein

SKP:

S-phase kinase-associated protein

TGF-β:

Transforming growth factor beta

Treg:

T-regulatory cells

WT:

Wild type

References

  1. Li B, Greene MI (2007) FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. Cell Cycle 6(12):1432–1436

    Article  CAS  PubMed  Google Scholar 

  2. Allan SE, Passerini L, Bacchetta R, Crellin N, Dai M, Orban PC, Ziegler SF, Roncarolo MG, Levings MK (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 115(11):3276–3284

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Li B, Samanta A, Song X, Iacono KT, Bembas K, Tao R, Basu S, Riley JL, Hancock WW, Shen Y, Saouaf SJ, Greene MI (2007) FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci USA 104(11):4571–4576

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, Miyachi Y, Tsukada T, Sakaguchi S (2007) Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446(7136):685–689

    Article  CAS  PubMed  Google Scholar 

  5. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351–356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73

    Article  CAS  PubMed  Google Scholar 

  8. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106(12):R75–R81

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Blair PJ, Bultman SJ, Haas JC, Rouse BT, Wilkinson JE, Godfrey VL (1994) CD4+ CD8− T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol 153(8):3764–3774

    CAS  PubMed  Google Scholar 

  12. Godfrey VL, Wilkinson JE, Rinchik EM, Russell LB (1991) Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci USA 88(13):5528–5532

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276(40):37672–37679

    Article  CAS  PubMed  Google Scholar 

  14. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    Article  CAS  PubMed  Google Scholar 

  15. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  PubMed  Google Scholar 

  16. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, Banissi C, Galluzzi L, Kroemer G, Tartour E (2013) Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron 6(2):147–157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Whiteside TL (2014) Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother 63(1):67–72

    Article  CAS  PubMed  Google Scholar 

  18. Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30(1):531–564

    Article  CAS  PubMed  Google Scholar 

  19. Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241(1):260–268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10(7):490–500

    Article  CAS  PubMed  Google Scholar 

  21. 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):1151–1164

    CAS  PubMed  Google Scholar 

  22. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445(7129):766–770

    Article  CAS  PubMed  Google Scholar 

  24. Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11(2):119–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127(4):759–767

    CAS  PubMed  Google Scholar 

  26. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949

    Article  CAS  PubMed  Google Scholar 

  27. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787

    Article  CAS  PubMed  Google Scholar 

  29. Teng MW, Ritchie DS, Neeson P, Smyth MJ (2011) Biology and clinical observations of regulatory T cells in cancer immunology. Curr Top Microbiol Immunol 344:61–95

    CAS  PubMed  Google Scholar 

  30. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19(4):345–354

    Article  CAS  PubMed  Google Scholar 

  31. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911

    Article  CAS  PubMed  Google Scholar 

  32. Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38(3):414–423

    Article  CAS  PubMed  Google Scholar 

  33. Mahic M, Henjum K, Yaqub S, Bjørnbeth BA, Torgersen KM, Taskén K, Aandahl EM (2008) Generation of highly suppressive adaptive CD8+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation. Eur J Immunol 38(3):640–646

    Article  CAS  PubMed  Google Scholar 

  34. Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC (2005) TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest 115(10):2904–2913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Jarvis LB, Matyszak MK, Duggleby RC, Goodall JC, Hall FC, Gaston JSH (2005) Autoreactive human peripheral blood CD8+ T cells with a regulatory phenotype and function. Eur J Immunol 35(10):2896–2908

    Article  CAS  PubMed  Google Scholar 

  36. Billerbeck E, Blum HE, Thimme R (2007) Parallel expansion of human virus-specific FoxP3−effector memory and De novo-generated FoxP3+ regulatory CD8+ T Cells upon antigen recognition in vitro. J Immunol 179(2):1039–1048

    Article  CAS  PubMed  Google Scholar 

  37. Joosten SA, van Meijgaarden KE, Savage NDL, de Boer T, Triebel F, van der Wal A, de Heer E, Klein MR, Geluk A, Ottenhoff THM (2007) Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc Natl Acad Sci 104(19):8029–8034

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S, Annunziato F (2003) Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102(12):4107–4114

    Article  CAS  PubMed  Google Scholar 

  39. Rifa’i M, Kawamoto Y, Nakashima I, Suzuki H (2004) Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J Exp Med 200(9):1123–1134

    Article  PubMed Central  PubMed  Google Scholar 

  40. Holler PD, Yamagata T, Jiang W, Feuerer M, Benoist C, Mathis D (2007) The same genomic region conditions clonal deletion and clonal deviation to the CD8alphaalpha and regulatory T cell lineages in NOD versus C57BL/6 mice. Proc Natl Acad Sci USA 104(17):7187–7192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Mayer CT, Floess S, Baru AM, Lahl K, Huehn J, Sparwasser T (2011) CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity. Eur J Immunol 41(3):716–725

    Article  CAS  PubMed  Google Scholar 

  42. Monteiro M, Almeida CF, Caridade M, Ribot JC, Duarte J, Agua-Doce A, Wollenberg I, Silva-Santos B, Graca L (2010) Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-β. J Immunol 185(4):2157–2163

    Article  CAS  PubMed  Google Scholar 

  43. Moreira-Teixeira L, Resende M, Devergne O, Herbeuval JP, Hermine O, Schneider E, Dy M, Cordeiro-da-Silva A, Leite-de-Moraes MC (2012) Rapamycin combined with TGF-beta converts human invariant NKT cells into suppressive Foxp3+ regulatory cells. J Immunol 188(2):624–631

    Article  CAS  PubMed  Google Scholar 

  44. Chang X, Gao JX, Jiang Q, Wen J, Seifers N, Su L, Godfrey VL, Zuo T, Zheng P, Liu Y (2005) The scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis. J Exp Med 202(8):1141–1151

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Liston A, Farr AG, Chen Z, Benoist C, Mathis D, Manley NR, Rudensky AY (2007) Lack of Foxp3 function and expression in the thymic epithelium. J Exp Med 204(3):475–480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Chen GY, Chen C, Wang L, Chang X, Zheng P, Liu Y (2008) Cutting edge: broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol 180(8):5163–5166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, Liu Y, Wang Y, Liu X, Chan MW, Liu JQ, Love R, Liu CG, Godfrey V, Shen R, Huang TH, Yang T, Park BK, Wang CY, Zheng P (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129(7):1275–1286

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Zuo T, Liu R, Zhang H, Chang X, Liu Y, Wang L, Zheng P (2007) FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest 117(12):3765–3773

    CAS  PubMed Central  PubMed  Google Scholar 

  49. McInnes N, Sadlon TJ, Brown CY, Pederson S, Beyer M, Schultze JL, McColl S, Goodall GJ, Barry SC (2012) FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells. Oncogene 31(8):1045–1054

    Article  CAS  PubMed  Google Scholar 

  50. Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, McNally B, Lin L, Zhou P, Zuo T, Cooney KA, Liu Y, Zheng P (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16(4):336–346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Li W, Katoh H, Wang L, Yu X, Du Z, Yan X, Zheng P, Liu Y (2013) FOXP3 regulates sensitivity of cancer cells to irradiation by transcriptional repression of BRCA1. Cancer Res 73(7):2170–2180

    Article  CAS  PubMed  Google Scholar 

  52. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27(11):1746–1752

    Article  CAS  PubMed  Google Scholar 

  53. Ladoire S, Arnould L, Mignot G, Coudert B, Rebe C, Chalmin F, Vincent J, Bruchard M, Chauffert B, Martin F, Fumoleau P, Ghiringhelli F (2011) Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 125(1):65–72

    Article  CAS  PubMed  Google Scholar 

  54. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, Grutzmann R, Pilarsky C, Ungefroren H, Saeger HD, Kloppel G, Kabelitz D, Kalthoff H (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67(17):8344–8350

    Article  CAS  PubMed  Google Scholar 

  55. Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, Gedye C, Moss D, Ng SP, MacGregor D, Davis ID, Cebon J, Chen W (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68(8):3001–3009

    Article  CAS  PubMed  Google Scholar 

  56. Xia M, Zhao M-Q, Wu K, X-Y Lin, Liu Y, Y-J Qin (2013) Investigations on the clinical significance of FOXP3 protein expression in cervical oesophageal cancer and the number of FOXP3+ tumour-infiltrating lymphocytes. J Intl Med Res 41(4):1002–1008

    Article  CAS  Google Scholar 

  57. Yoshii M, Tanaka H, Ohira M, Muguruma K, Iwauchi T, Lee T, Sakurai K, Kubo N, Yashiro M, Sawada T, Hirakawa K (2012) Expression of Forkhead box P3 in tumour cells causes immunoregulatory function of signet ring cell carcinoma of the stomach. Br J Cancer 106(10):1668–1674

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Hao Q, Li W, Zhang C, Qin X, Xue X, Li M, Shu Z, Xu T, Xu Y, Wang W, Zhang W, Zhang Y (2013) TNFα induced FOXP3–NFκB interaction dampens the tumor suppressor role of FOXP3 in gastric cancer cells. Biochem Biophys Res Commun 430(1):436–441

    Article  CAS  PubMed  Google Scholar 

  59. Lal A, Chan L, DeVries S, Chin K, Scott G, Benz C, Chen Y-Y, Waldman F, Hwang ES (2013) FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast. Breast Cancer Res Treat 139(2):381–390

    Article  CAS  PubMed  Google Scholar 

  60. Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T, Barda AK, Gourgoulianis KI, Germenis AE (2008) Foxp3 expression in human cancer cells. J Transl Med 6:19

    Article  PubMed Central  PubMed  Google Scholar 

  61. Miranda-Hernandez DF, Franco-Molina MA, Mendoza-Gamboa E, Zapata-Benavides P, Sierra-Rivera CA, Coronado-Cerda EE, Rosas-Taraco AG, Tamez-Guerra RS, Rodriguez-Padilla C (2013) Expression of Foxp3, CD25 and IL-2 in the B16F10 cancer cell line and melanoma is correlated with tumor growth in mice. Oncol Lett 6(5):1195–1200

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22(3):329–341

    Article  CAS  PubMed  Google Scholar 

  63. Kim J, Lahl K, Hori S, Loddenkemper C, Chaudhry A, deRoos P, Rudensky A, Sparwasser T (2009) Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. J Immunol 183(12):7631–7634

    Article  CAS  PubMed  Google Scholar 

  64. Droeser RA, Obermann EC, Wolf AM, Wallner S, Wolf D, Tzankov A (2013) Negligible nuclear FOXP3 expression in breast cancer epithelial cells compared with FOXP3-Positive T cells. Clin Breast Cancer 13(4):264–270

    Article  CAS  PubMed  Google Scholar 

  65. Courtney AE, C Doherty C, Herron B, McCarron MO, Connolly JK, Jefferson JA (2004) Acute polymyositis following renal transplantation. Am J Transpl 4(7):1204–1207

    Article  Google Scholar 

  66. Retraction. Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth (2011). J Exp Med 208 (12):2561

  67. Put S, Avau A, Humblet-Baron S, Schurgers E, Liston A, Matthys P (2012) Macrophages have no lineage history of Foxp3 expression. Blood 119(5):1316–1318

    Article  CAS  PubMed  Google Scholar 

  68. Mayer CT, Kuhl AA, Loddenkemper C, Sparwasser T (2012) Lack of Foxp3+ macrophages in both untreated and B16 melanoma-bearing mice. Blood 119(5):1314–1315

    Article  CAS  PubMed  Google Scholar 

  69. Li F, Yang M, Wang L, Williamson I, Tian F, Qin M, Shah PK, Sharifi BG (2012) Autofluorescence contributes to false-positive intracellular Foxp3 staining in macrophages: a lesson learned from flow cytometry. J Immunol Methods 386(1–2):101–107

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Devaud C, Westwood JA, John LB, Flynn JK, Paquet-Fifield S, Duong CP, Yong CS, Pegram HJ, Stacker SA, Achen MG, Stewart TJ, Snyder LA, Teng MW, Smyth MJ, Darcy PK, Kershaw MH (2014) Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. Mol Ther 22(1):18–27

    Article  CAS  PubMed  Google Scholar 

  71. Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V (2003) Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 63(23):8408–8413

    CAS  PubMed  Google Scholar 

  72. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115(12):3623–3633

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Colombo MP, Piconese S (2007) Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer 7(11):880–887

    Article  CAS  PubMed  Google Scholar 

  74. Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8(3):277–284

    Article  CAS  PubMed  Google Scholar 

  75. Casares N, Rudilla F, Arribillaga L, Llopiz D, Riezu-Boj JI, Lozano T, Lopez-Sagaseta J, Guembe L, Sarobe P, Prieto J, Borras-Cuesta F, Lasarte JJ (2010) A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice. J Immunol 185(9):5150–5159

    Article  CAS  PubMed  Google Scholar 

  76. Morse MA, Hobeika A, Serra D, Aird K, McKinney M, Aldrich A, Clay T, Mourich D, Lyerly HK, Iversen PL, Devi GR (2012) Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function. Cancer Gene Ther 19(1):30–37

    Article  CAS  PubMed  Google Scholar 

  77. Nair S, Boczkowski D, Fassnacht M, Pisetsky D, Gilboa E (2007) Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67(1):371–380

    Article  CAS  PubMed  Google Scholar 

  78. Xiao Y, Li B, Zhou Z, Hancock WW, Zhang H, Greene MI (2010) Histone acetyltransferase mediated regulation of FOXP3 acetylation and Treg function. Curr Opin Immunol 22(5):583–591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Liu Y, Wang L, Predina J, Han R, Beier UH, Wang LC, Kapoor V, Bhatti TR, Akimova T, Singhal S, Brindle PK, Cole PA, Albelda SM, Hancock WW (2013) Inhibition of p300 impairs Foxp3(+) T regulatory cell function and promotes antitumor immunity. Nat Med 19(9):1173–1177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Nair S, Aldrich AJ, McDonnell E, Cheng Q, Aggarwal A, Patel P, Williams MM, Boczkowski D, Lyerly HK, Morse MA, Devi GR (2013) Immunologic targeting of FOXP3 in inflammatory breast cancer cells. PLoS One 8(1):e53150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 30:733–758

    Article  CAS  PubMed  Google Scholar 

  82. Triulzi T, Tagliabue E, Balsari A, Casalini P (2013) FOXP3 expression in tumor cells and implications for cancer progression. J Cell Physiol 228(1):30–35

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by funding from the National Health and Medical Research Council of Australia and the Cancer Council of Victoria.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia

    Christel Devaud, Phillip K. Darcy & Michael H. Kershaw

  2. Department of Immunology, Monash University, Prahran, VIC, 3181, Australia

    Phillip K. Darcy & Michael H. Kershaw

  3. Cancer Immunology Research Program, Peter MacCallum Cancer Center, Saint Andrews Place, Melbourne, VIC, 3002, Australia

    Christel Devaud & Michael H. Kershaw

Authors
  1. Christel Devaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Phillip K. Darcy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael H. Kershaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christel Devaud or Michael H. Kershaw.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Devaud, C., Darcy, P.K. & Kershaw, M.H. Foxp3 expression in T regulatory cells and other cell lineages. Cancer Immunol Immunother 63, 869–876 (2014). https://doi.org/10.1007/s00262-014-1581-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1581-4

Keywords

Search

Navigation