Cancer Immunology, Immunotherapy

, Volume 63, Issue 8, pp 835–845 | Cite as

Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy

  • Jungsun Park
  • Haiyan Li
  • Mingjun Zhang
  • Yong Lu
  • Bangxing Hong
  • Yuhuan Zheng
  • Jin He
  • Jing Yang
  • Jianfei Qian
  • Qing YiEmail author
Original Article


Dendritic cells (DCs) are professional antigen-presenting cells to initiate immune responses, and DC survival time is important for affecting the strength of T-cell responses. Interleukin (IL)-9-producing T-helper (Th)-9 cells play an important role in anti-tumor immunity. However, it is unclear how Th9 cells communicate with DCs. In this study, we investigated whether murine Th9 cells affected the survival of myeloid DCs. DCs derived from bone marrow of C57BL/6 mice were cocultured with Th9 cells from OT-II mice using transwell, and the survival of DCs was examined. DCs cocultured with Th9 cells had longer survival and fewer apoptotic cells than DCs cultured alone in vitro. In melanoma B16-OVA tumor-bearing mice, DCs conditioned by Th9 cells lived longer and induced stronger anti-tumor response than control DCs did in vivo. Mechanistic studies revealed that IL-3 but not IL-9 secreted by Th9 cells was responsible for the prolonged survival of DCs. IL-3 upregulated the expression of anti-apoptotic protein Bcl-xL and activated p38, ERK and STAT5 signaling pathways in DCs. Taken together, our data provide the first evidence that Th9 cells can promote the survival of DCs through IL-3, and will be helpful for designing Th9 cell immunotherapy and more effective DC vaccine for human cancers.


Th9 cells Dendritic cells Survival IL-3 Cancer immunotherapy 





Bone marrow


5(6)-Carboxyfluorescein diacetate succinimidyl ester


Dendritic cells


Granulocyte–macrophage colony-stimulating factor


Interferon gamma






Phorbol myristate acetate




Transforming growth factor


Tumor necrosis factor



This work was supported by grants from the National Cancer Institute (R01 CA96569, R01 CA103978, R01 CA138402 and P50 CA142509), the Leukemia & Lymphoma Society and Multiple Myeloma Research Foundation.

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

262_2014_1557_MOESM1_ESM.pdf (202 kb)
Supplementary material 1 (PDF 201 kb)


  1. 1.
    Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12(4):265–277. doi: 10.1038/nrc3258 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Heath WR, Carbone FR (2013) The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol 14(10):978–985. doi: 10.1038/ni.2680 PubMedCrossRefGoogle Scholar
  3. 3.
    Matthews KE, Qin JS, Yang J, Hermans IF, Palmowski MJ, Cerundolo V, Ronchese F (2007) Increasing the survival of dendritic cells in vivo does not replace the requirement for CD4+ T cell help during primary CD8+ T cell responses. J Immunol 179(9):5738–5747PubMedCrossRefGoogle Scholar
  4. 4.
    Kamath AT, Pooley J, O’Keeffe MA, Vremec D, Zhan Y, Lew AM, D’Amico A, Wu L, Tough DF, Shortman K (2000) The development, maturation, and turnover rate of mouse spleen dendritic cell populations. J Immunol 165(12):6762–6770PubMedCrossRefGoogle Scholar
  5. 5.
    Park Y, Lee SW, Sung YC (2002) Cutting edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-3′-OH kinase pathway. J Immunol 168(1):5–8PubMedCrossRefGoogle Scholar
  6. 6.
    Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P (1998) Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 188(11):2175–2180PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I, Banchereau J (1994) Activation of human dendritic cells through CD40 cross-linking. J Exp Med 180(4):1263–1272PubMedCrossRefGoogle Scholar
  8. 8.
    Josien R, Li HL, Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y (2000) TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 191(3):495–502PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Miga AJ, Masters SR, Durell BG, Gonzalez M, Jenkins MK, Maliszewski C, Kikutani H, Wade WF, Noelle RJ (2001) Dendritic cell longevity and T cell persistence is controlled by CD154-CD40 interactions. Eur J Immunol 31(3):959–965. doi: 10.1002/1521-4141(200103)31:3<959:AID-IMMU959>3.0.CO;2-A PubMedCrossRefGoogle Scholar
  10. 10.
    Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 9(12):1347–1355. doi: 10.1038/ni.1677 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, McKinley C, Ahyi AN, Han L, Nguyen ET, Robertson MJ, Perumal NB, Tepper RS, Nutt SL, Kaplan MH (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11(6):527–534. doi: 10.1038/ni.1867 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202. doi: 10.1016/j.immuni.2010.07.014 PubMedCrossRefGoogle Scholar
  13. 13.
    Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346. doi: 10.1038/ni.1659 PubMedCrossRefGoogle Scholar
  14. 14.
    Lu Y, Hong S, Li H, Park J, Hong B, Wang L, Zheng Y, Liu Z, Xu J, He J, Yang J, Qian J, Yi Q (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122(11):4160–4171. doi: 10.1172/JCI65459 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18(8):1248–1253. doi: 10.1038/nm.2856 PubMedCrossRefGoogle Scholar
  16. 16.
    Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252(1):104–115. doi: 10.1111/imr.12028 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Soroosh P, Doherty TA (2009) Th9 and allergic disease. Immunology 127(4):450–458. doi: 10.1111/j.1365-2567.2009.03114.x PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Park JS, Sohn HJ, Park GS, Chung YJ, Kim TG (2011) Induction of antitumor immunity using dendritic cells electroporated with polo-like kinase 1 (Plk1) mRNA in murine tumor models. Cancer Sci 102(8):1448–1454. doi: 10.1111/j.1349-7006.2011.01974.x PubMedCrossRefGoogle Scholar
  19. 19.
    Reddy EP, Korapati A, Chaturvedi P, Rane S (2000) IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 19(21):2532–2547. doi: 10.1038/sj.onc.1203594 PubMedCrossRefGoogle Scholar
  20. 20.
    Yen JJ, Yang-Yen HF (2006) Transcription factors mediating interleukin-3 survival signals. Vitam Horm 74:147–163. doi: 10.1016/S0083-6729(06)74006-7 PubMedCrossRefGoogle Scholar
  21. 21.
    Wilhelm C, Turner JE, Van Snick J, Stockinger B (2012) The many lives of IL-9: a question of survival? Nat Immunol 13(7):637–641. doi: 10.1038/ni.2303 PubMedCrossRefGoogle Scholar
  22. 22.
    Robb L (2007) Cytokine receptors and hematopoietic differentiation. Oncogene 26(47):6715–6723. doi: 10.1038/sj.onc.1210756 PubMedCrossRefGoogle Scholar
  23. 23.
    Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, Bonder CS, Lopez AF, Parker MW (2012) The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol Rev 250(1):277–302. doi: 10.1111/j.1600-065X.2012.01164.x PubMedCrossRefGoogle Scholar
  24. 24.
    Ebner S, Hofer S, Nguyen VA, Furhapter C, Herold M, Fritsch P, Heufler C, Romani N (2002) A novel role for IL-3: human monocytes cultured in the presence of IL-3 and IL-4 differentiate into dendritic cells that produce less IL-12 and shift Th cell responses toward a Th2 cytokine pattern. J Immunol 168(12):6199–6207PubMedCrossRefGoogle Scholar
  25. 25.
    Buelens C, Bartholome EJ, Amraoui Z, Boutriaux M, Salmon I, Thielemans K, Willems F, Goldman M (2002) Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. Blood 99(3):993–998PubMedCrossRefGoogle Scholar
  26. 26.
    Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, Briere F, de Waal Malefyt R, Liu YJ (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283(5405):1183–1186PubMedCrossRefGoogle Scholar
  27. 27.
    Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 185(6):1101–1111PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Hou WS, Van Parijs L (2004) A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells. Nat Immunol 5(6):583–589. doi: 10.1038/ni1071 PubMedCrossRefGoogle Scholar
  29. 29.
    Dumon S, Santos SC, Debierre-Grockiego F, Gouilleux-Gruart V, Cocault L, Boucheron C, Mollat P, Gisselbrecht S, Gouilleux F (1999) IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line. Oncogene 18(29):4191–4199. doi: 10.1038/sj.onc.1202796 PubMedCrossRefGoogle Scholar
  30. 30.
    Chen M, Wang YH, Wang Y, Huang L, Sandoval H, Liu YJ, Wang J (2006) Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311(5764):1160–1164. doi: 10.1126/science.1122545 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jungsun Park
    • 1
  • Haiyan Li
    • 1
    • 2
  • Mingjun Zhang
    • 1
    • 2
  • Yong Lu
    • 1
    • 2
  • Bangxing Hong
    • 1
    • 2
  • Yuhuan Zheng
    • 1
    • 2
  • Jin He
    • 1
  • Jing Yang
    • 1
  • Jianfei Qian
    • 1
    • 2
  • Qing Yi
    • 1
    • 2
    Email author
  1. 1.Department of Lymphoma and Myeloma, Division of Cancer Medicine, and Center for Cancer Immunology ResearchThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Cancer Biology, Lerner Research InstituteCleveland ClinicClevelandUSA

Personalised recommendations