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FoxP3 Expression in Macrophages, Cancer, and B Cells—Is It Real?

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Abstract

During the last decade, B regulatory cells are appreciated to have a central role in preventing autoimmunity and maintaining self-tolerance. They are characterized by expressing different phenotypic markers and the production of either IL-10 or TGF-β or both. The recent recognition of Fas ligand expressing B regulatory cells as “killer” cells established their role in maintaining viral persistence by preventing effective antiviral immune responses. The forkhead lineage-transcription factor (FoxP3) was considered for many years to be a highly specific intracellular regulatory marker of CD4+CD25+ T regulatory cells. The possibility of FoxP3 being expressed in B regulatory cells was suggested in many studies. Though controversial, FoxP3 expression was also reported in macrophages and cancer cells. Aiming to avoid artifact staining, many researchers required the usage of FoxP3 messenger RNA (mRNA) and PCR in order to prove a true expression of FoxP3 in these different cells. In addition, most studies’ report on that FoxP3 expression in all abovementioned cells is related to their status of activation since naïve (non-activated cells) were found poorly FoxP3 expressing. In this review, we present the existing data on FoxP3 expression in non-T-regulatory cells, but we suggest that further studies are needed to better establish this concept.

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References

  1. Wolf S, Dittel B, Hardardotti F, Janeway C (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 184:2271–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fillatreau S, Sweenie C, Mcgeachy M, Gray D, Anderton S (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–50

    Article  CAS  PubMed  Google Scholar 

  3. Brisslert M, Bokarewa M, Larsson P, Wing K, Collins LV, Tarkowski A (2006) Phenotypic and functional characterization of human CD25+ B cells. Immunology 117:548–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Amu S, Tarkowski A, Dorner T, Bokarewa M, Brisslert M (2007) The human immunomodulatory CD25+B cell population belongs to the memory B cell pool. Scan J Immunol 66:77–86

    Article  CAS  Google Scholar 

  5. Lampropoulou V, Hoehlig K, Roch T, Neves P, Calderon Gomez E, Sweenie CH et al (2008) TLR-activated B cells suppress T cell mediated autoimmunity. J Immunol 180:4763–73

    Article  CAS  PubMed  Google Scholar 

  6. Tedder TF, Leonard WJ (2014) Autoimmunity: regulatory B cells- IL-35 and IL-21 regulate the regulators. Nat Rev Rheumatol 10:452–3

    Article  CAS  PubMed  Google Scholar 

  7. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV et al (2014) Interleukin-35 induces B cells that suppress autoimmune disease. Nat Med 20:633–41

    Article  PubMed  PubMed Central  Google Scholar 

  8. Eriksson P, Sandell C, Backteman K, Ernerudh J (2010) B cell abnormalities in Wegener’s granulomatosis and microscopic polyangiitis: role of CD25+expressing B cells. J Rheumatol 37:2086–95

    Article  PubMed  Google Scholar 

  9. Aybar LT, McGregor JG, Hogan SL, Hu Y, Mendoza CE, Brant EJ, Poulton CJ et al (2015) Reduced CD5+ CD24highCD38high and interleukin 10+ regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies. Clin Exp Immunol 180:178–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Todd SK, Pepper RJ, Draibe J, Tanna A, Pusey CD, Mauri C, Salama AD (2014) Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 53:1693–703

    Article  Google Scholar 

  11. Kessel A, Haj T, Peri R, Snir A, Melamed D, Sabo E, Toubi E (2012) Human CD19+CD25high B regulatory cells suppress proliferation of CD4+ T cells and enhance FoxP3 and CTLA4 expression in T regulatory cells. Autoimmun Rev 11:670–77

    Article  CAS  PubMed  Google Scholar 

  12. Vadasz Z, Haj T, Halasz K, Rosner I, Slobodin G, Attias D, Kessel A et al (2012) Semaphorin 3A is a marker for disease activity and potential immunoregulator in systemic lupus erythematosus. Arthritis Res Ther 14:R146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C (2010) CD19+CD24highCD38high B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus. Immunity 32:129–140

    Article  CAS  PubMed  Google Scholar 

  14. Khoder A, Sarvaria A, Alsuliman A, Chew C, Sekine T, Cooper N et al (2014) Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD. Blood 124:2034–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nenon M, Blair PA, Isenberg DA, Mauri C (2016) A regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity 44:683–97

    Article  Google Scholar 

  16. DiLillo DJ, Matsushita T, Tedder TF (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci 1183:38–57

    Article  CAS  PubMed  Google Scholar 

  17. Watanabe R, Ishiura N, Nakashima H, Kuwano Y, Okochi H, Tamaki K et al (2010) Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol 184:4801–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zheng Z, Liu T, Li X, Ding J, Feng Y, Miao J et al (2015) Kinetic changes of regulatory B10 cells in collagen-induced arthritis could be regulated by cytokines IFN-gamma and TGF-betta. Inflamm Res 64:637–45

    Article  CAS  PubMed  Google Scholar 

  19. Sheng JR, Quan S, Soliven B (2014) CD1dhigh CD5+ B cells expanded by GM-CSF in vivo suppress experimental autoimmune myasthenia gravis. J Immunol 193:2669–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Daien CI, Gailhac S, Mura T, Audo R, Combe B, Hahne M, Morel J (2014) Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol 66:2037–46

    Article  CAS  PubMed  Google Scholar 

  21. Hayashi M, Yanaba K, Umezawa Y, Yoshihara Y, Kikuchi S, Ishiuji Y et al (2016) IL-10-producing regulatory B cells are decreased in patients with psoriasis. J Dermatol Sci 81:93–100

    Article  CAS  PubMed  Google Scholar 

  22. Mavropoulos A, Simopoulou T, Varna A, Liaskos C, Kataiari CG, Bogdanos DP, Sakkas LI (2016) Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol 68:494–504

    Article  CAS  PubMed  Google Scholar 

  23. Lundy SK, Klinker MW (2014) Characterization and activity of Fas ligand producing CD5+ B cells. Methods Mol Biol 1190:81–102

    Article  CAS  PubMed  Google Scholar 

  24. Lundy SK, Boros DL (2002) Fas ligand expressing B-1a lymphocytes mediate CD4+ T cell apoptosis during schistosomal infection: induction by interleukin 4 and 10. Infect Immun 70:812–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL (2001) Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 167:1081–9

    Article  CAS  PubMed  Google Scholar 

  26. Akdis M, Trautmann A, Klunker S, Daigle I, Kucuksezer UC, Deglman W et al (2003) T helper 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J 17:1026–35

    Article  CAS  PubMed  Google Scholar 

  27. Hagn M, Ebel V, Sontheimer K, Schwesinger E, Lunov O, Beyer T et al (2010) CD5+ B cells from individuals with systemic lupus erythematosus express granzyme B. Eur J Immunol 40:2060–9

    Article  CAS  PubMed  Google Scholar 

  28. Lourenco EV, La Cava A (2011) Natural regulatory T cells in autoimmunity. Autoimmunity 44:33–42

    Article  CAS  PubMed  Google Scholar 

  29. Kuhn A, Beissert S, Krammer PH (2009) CD4+CD25+ regulatory T cells in human lupus erythematosus. Arch Dermatol Res 301:71–81

    Article  PubMed  Google Scholar 

  30. Buckner JH (2010) Mechanisms of impaired regulation by CD4+CD25+FoxP3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10:849–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S (2008) Dysfunctional CD4+CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum 58:801–12

    Article  CAS  PubMed  Google Scholar 

  32. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, Toubi E (2007) Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 176:5571–5

    Article  Google Scholar 

  33. Kikuchi J, Hashizume M, Kaneko Y, Yoshimoto K, Nishina N, Takeuchi T (2015) Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response. Arthritis Res Ther 17:10

    Article  PubMed  PubMed Central  Google Scholar 

  34. Horwitz DA (2010) Identity of mysterious CD4+CD25-FoxP3+ cells in SLE. Arthritis Res Ther 12:101

    Article  PubMed  PubMed Central  Google Scholar 

  35. Katoh H, Zheng P, Liu Y (2013) FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 41:72–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chu R et al (2015) Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells. Mol Cell Endocrinology 399:228–234

    Article  CAS  Google Scholar 

  37. Zuo T, Wang L, Morrison C et al (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hinz S, Pagerols-Raluy L, Oberg HH et al (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350

    Article  CAS  PubMed  Google Scholar 

  39. Wang L, Liu R, Li W et al (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16:336–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3 tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18:3022–9

    Article  CAS  PubMed  Google Scholar 

  41. Casares N, Rudilla F, Arribillaga L et al (2010) A peptide inhibitor of FoxP3 impairs regulatory T cell activity and improves vaccine efficacy in mice. J Immunol 185:5150–9

    Article  CAS  PubMed  Google Scholar 

  42. Zuo T, Liu R, Zhang H et al (2007) FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest 117:3765–3773

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang HY, Sun H (2010) Up-regulation of Foxp3 inhibits cell proliferation, migration and invasion in epithelial ovarian cancer. Cancer Lett 287:91–97

    Article  CAS  PubMed  Google Scholar 

  44. Martin F, Ladoire S, Mignot G, Apetoh L, Ghiringhelli F (2010) Human FOXP3 and cancer. Oncogene 29:4121–4129

    Article  CAS  PubMed  Google Scholar 

  45. Bohling SD, Allison KH (2008) Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol 21:1527–1532

    Article  CAS  PubMed  Google Scholar 

  46. Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M (2009) Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 58:441–447

    Article  CAS  PubMed  Google Scholar 

  47. Ladoire S, Arnould L, Mignot G et al (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 125:65–72

    Article  CAS  PubMed  Google Scholar 

  48. Merlo A, Casalini P, Carcangiu ML et al (2009) FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27:1746–1752

    Article  CAS  PubMed  Google Scholar 

  49. Tao H, Mimura Y, Aoe K et al (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75:95–101

    Article  PubMed  Google Scholar 

  50. Winerdal ME, Marits P, Winerdal M et al (2011) FOXP3 and survival in urinary bladder cancer. BJU Int 108:1672–1678

    Article  CAS  PubMed  Google Scholar 

  51. Laheru D, Jaffee EM (2005) Immunotherapy for pancreatic cancer—science driving clinical progress. Nat Rev Cancer 5:459–67

    Article  CAS  PubMed  Google Scholar 

  52. Schniewind B, Groth S, Sebens Muerkoster S et al (2007) Dissecting the role of TGF-h type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function. Oncogene 26(33):4850–62, Epub 2007 Feb 12

    Article  CAS  PubMed  Google Scholar 

  53. Zhou Z, Song X, Li B, Greene MI (2008) FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. Immunol Res 42:19–28

    Article  CAS  PubMed  Google Scholar 

  54. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  CAS  PubMed  Google Scholar 

  55. Nicolini A, Carpi A, Rossi G (2006) Cytokines in breast cancer. Cytokine Growth Factor Rev 17:325–337

    Article  CAS  PubMed  Google Scholar 

  56. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-h induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad 7. J Immunol 172:5149–53

    Article  CAS  PubMed  Google Scholar 

  57. Chen W, Jin W, Hardegen N et al (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-h induction of transcription factor Foxp3. J Exp Med 198:1875–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lipscomb MW, Taylor JL, Goldbach CJ, Watkins SC, Wesa AK, Storkus WJ (2010) DC expressing transgene FoxP3 are regulatory APC. Eur J Immunol 40:480–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Manrique SZ, Correa MA, Hoelzinger DB, Dominguez AL, Mirza N et al (2011) FoxP3+ macrophages display immunosuppressive properties and promote tumor growth. J Exp Med 208:1485–99

    Article  CAS  PubMed  Google Scholar 

  60. Put S, Avau A, Humblet-Baron S, Schurgers E, Liston A, Matthys P (2012) Macrophages have no lineage history of FoxP3 expression. Blood 119:1316–18

    Article  CAS  PubMed  Google Scholar 

  61. Devaud C, Yong CSM, John LB, Westwood JA, Duong C, House CH, Denoyer D et al (2014) FoxP3 expression in macrophages associated with RENCA tumors in mice. PLoS One 9:e108670

    Article  PubMed  PubMed Central  Google Scholar 

  62. Vadasz Z, Toubi E (2014) The many faces of B regulatory cells. Isr Med Assoc J 16:631–3

    PubMed  Google Scholar 

  63. Noh J, Noh G (2012) Allergen-specific responses of CD19high and CD19low B cells in non-IgE mediated food allergy of late eczematous reactions in atopic dermatitis: presence of IL-17-and IL-32 producing regulatory B cells (Br17 & Br32). Inflam Allergy Drug Targets 11:320

    Article  CAS  Google Scholar 

  64. Noh J, Noh G, Kim HS, Kim AR, Choi WS (2012) Allergen-specific responses of CD19+CD5+FoxP3+ regulatory B cells and CD4+FoxP3+ regulatory T cell in immune tolerance of cow milk allergy of late eczematous reactions. Cell Immunol 274:109–14

    Article  CAS  PubMed  Google Scholar 

  65. de Andres C, Tejera-Alhambra M, Alonso B, Valor L, Teijerio R, Ramos-Medina R, Mateos D et al (2014) New regulatory CD10+CD25+ B-cell subset in clinically isolated syndrome and multiple sclerosis relapse. Changes after glucocorticoids. J Neuroimmunol 270:37–44

    Article  PubMed  Google Scholar 

  66. Guo Y, Zhang X, Qin M, Wang X (2015) Changes in peripheral CD19+FoxP3+ and CD19+TGF-beta+ regulatory B cell populations in rheumatoid arthritis patients with interstitial lung diseases. J Thorac Dis 7:471–77

    PubMed  PubMed Central  Google Scholar 

  67. Vadasz Z, Peri R, Eiza N, Slobodin G, Gurman-Balbir A, Toubi E (2015) The expansion of CD25highIL-10highFoxP3high B regulatory cells is in association with SLE disease activity. J Immun Res 2015:254245

    Google Scholar 

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  1. Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel

    Zahava Vadasz & Elias Toubi

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  1. Zahava Vadasz
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  2. Elias Toubi
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Correspondence to Zahava Vadasz.

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Vadasz, Z., Toubi, E. FoxP3 Expression in Macrophages, Cancer, and B Cells—Is It Real?. Clinic Rev Allerg Immunol 52, 364–372 (2017). https://doi.org/10.1007/s12016-016-8572-5

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