Abstract
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.
Similar content being viewed by others
Abbreviations
- Ab:
-
Antibody
- BM:
-
Bone marrow
- CFSE:
-
5(6)-Carboxyfluorescein diacetate succinimidyl ester
- DC:
-
Dendritic cells
- GM-CSF:
-
Granulocyte–macrophage colony-stimulating factor
- IFN-r :
-
Interferon gamma
- IL:
-
Interleukin
- OVA:
-
Ovalbumin
- PMA:
-
Phorbol myristate acetate
- Th:
-
T-helper
- TGF:
-
Transforming growth factor
- TNF:
-
Tumor necrosis factor
References
Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12(4):265–277. doi:10.1038/nrc3258
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
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):5738–5747
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):6762–6770
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):5–8
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):2175–2180
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):1263–1272
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):495–502
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
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
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
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
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
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
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
Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252(1):104–115. doi:10.1111/imr.12028
Soroosh P, Doherty TA (2009) Th9 and allergic disease. Immunology 127(4):450–458. doi:10.1111/j.1365-2567.2009.03114.x
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
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
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
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
Robb L (2007) Cytokine receptors and hematopoietic differentiation. Oncogene 26(47):6715–6723. doi:10.1038/sj.onc.1210756
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
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):6199–6207
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):993–998
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):1183–1186
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):1101–1111
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
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
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
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Jungsun Park and Haiyan Li have contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Park, J., Li, H., Zhang, M. et al. Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunol Immunother 63, 835–845 (2014). https://doi.org/10.1007/s00262-014-1557-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-014-1557-4