[en] The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naive mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Mayer, Alice; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Debuisson, Delphine; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Denanglaire, Sebastien; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Eddahri, Fouad; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Fievez, Laurence ; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Hercor, Melanie; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Triffaux, Emily; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Moser, Muriel; Université Libre de Bruxelles - ULB > Laboratoire d’Immunobiologie, Institut de Biologie et de Médecine Moléculaire
Bureau, Fabrice ; Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Joffre, O., Nolte, M. A., Sporri, R. and Reis e Sousa, C., Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol. Rev. 2009. 227:234-247.
Maldonado-Lopez, R., De Smedt, T., Michel, P., Godfroid, J., Pajak, B., Heirman, C., Thielemans, K. et al., CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 1999. 189:587-592.
Pulendran, B., Smith, J. L., Caspary, G., Brasel, K., Pettit, D., Maraskovsky, E. and Maliszewski, C. R., Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl. Acad. Sci. USA 1999. 96:1036-1041.
Sokol, C. L., Chu, N. Q., Yu, S., Nish, S. A., Laufer, T. M. and Medzhitov, R., Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 2009. 10:713-720.
Perrigoue, J. G., Saenz, S. A., Siracusa, M. C., Allenspach, E. J., Taylor, B. C., Giacomin, P. R., Nair, M. G. et al., MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat. Immunol. 2009. 10:697-705.
Yoshimoto, T., Yasuda, K., Tanaka, H., Nakahira, M., Ima, Y., Fujimori, Y. and Nakanishi, K., Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat. Immunol. 2009. 10:706-712.
Hammad, H., Plantinga, M., Deswarte, K., Pouliot, P., Willart, M. A., Kool, M., Muskens, F. et al., Inflammatory dendritic cells-not basophils-are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J. Exp. Med. 2010. 207:2097-2111.
Tang, H., Cao, W., Kasturi, S. P., Ravindran, R., Nakaya, H. I., Kundu, K., Murthy, N. et al., The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat. Immunol. 2010. 11:608-617.
Gao, Y., Nish, S. A., Jiang, R., Hou, L., Licona-Limón, P., Weinstein, J. S., Zhao H. et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 2013. 39:722-732.
Kumamoto, Y., Linehan, M., Weinstein, J. S., Laidlaw, B. J., Craft, J. E. and Iwasaki, A., CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 2013. 39:733-743.
Plantinga, M., Guilliams, M., Vanheerswynghels, M., Deswarte, K., Branco-Madeira, F., Toussaint, W., Vanhoutte, L. et al., Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 2013. 38:322-335.
Murakami, R., Denda-Nagai, K., Hashimoto, S., Nagai, S., Hattori, M. and Irimura, T., A unique dermal dendritic cell subset that skews the immune response toward Th2. PLoS One 2013. 8:e73270.
Moser, M. and Murphy, K. M., Dendritic cell regulation of TH1-TH2 development. Nat. Immunol. 2000. 1:199-205.
Jenkins S. J., Perona-Wright, G., Worsley, A. G., Ishii, N. and MacDonald, A. S., Dendritic cell expression of OX40 ligand acts as a costimulatory, not polarizing, signal for optimal Th2 priming and memory induction in vivo. J. Immunol. 2007. 179:3515-3523.
Gonzalo, J. A., Tian, J., Delaney, T., Corcoran, J., Rottman, J. B., Lora, J., Al-garawia, A. et al., ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nat. Immunol. 2001. 2:597-604.
Amsen, D., Blander, J. M., Lee, G. R., Tanigaki K., Honjo T. and Flavell, R. A., Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004. 117:515-526.
Feng, B. S., Chen, X., He, S. H., Zheng, P. Y., Foster, J., Xing, Z., Bienenstock, J. et al., Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model. J. Allergy Clin. Immunol. 2008. 122:55-61.
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. and Stockinger, B., TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006. 24:179-89.
Nurieva, R. I., Chung, Y., Hwang, D., Yang, X. O., Kang, H. S., Ma, L., Wang, Y. et al., Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008. 29:138-149.
Eddahri, F., Denanglaire, S., Bureau, F., Spolski, R., Leonard, W. J., Leo, O. and Andris, F., Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 2009. 113:2426-2433.
Rincon, M., Anguita, J., Nakamura, T., Fikrig, E. and Flavell, R. A., Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J. Exp. Med. 1997. 185:461-469.
Dieh, S., Chow, C. W., Weiss, L., Palmetshofer, A., Twardzik, T., Rounds, L., Serfling, E. et al., Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J. Exp. Med. 2002. 196:39-49.
Yang, Y., Ochando, J., Yopp, A., Bromberg, J. S. and Ding, Y., IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation. J. Immunol. 2005. 174:2720-2729.
Doganci, A., Eigenbrod, T., Krug, N., De Sanctis, G. T., Hausding, M., Erpenbeck, V. J., Haddad, el B. et al., The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J. Clin. Invest. 2005. 115:313-325.
Wang, J., Homer, R. J., Chen, Q. and Elias J. A., Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation. J. Immunol. 2000. 165:4051-4061.
Smith, K. A. and Maizels, R. M., IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo. Eur. J. Immunol. 2014. 44:150-161.
Perona-Wright, G., Jenkins, S. J., O'Connor, R. A., Zienkiewicz, D., McSorley, H. J., Maizels, R. M., Anderton, S. M. et al., A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo. J. Immunol. 2009. 182:2808-2815.
Lambrecht, B. N., De. Veerman, M., Coyle, A. J., Gutierrez-Ramos, J. C., Thielemans, K. and Pauwels, R. A., Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 2000. 106:551-559.
Henry, E., Desmet, C. J., Garze, V., Fievez, L., Bedoret, D., Heirman, C., Faisca, P. et al., Dendritic cells genetically engineered to express IL-10 induce long-lasting antigen-specific tolerance in experimental asthma. J. Immunol. 2008. 181:7230-7242.
Diehl, S, Anguita, J., Hoffmeyer, A., Zapton, T., Ihle, J. N., Fikrig, E. and Rincon, M., Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 2000. 13:805-815.
Pulendran, B. and Artis, D., New paradigms in type 2 immunity. Science 2012. 337:431-435.
Kool, M., Petrilli, V., De Smedt, T., Rolaz, A., Hammad, H., van Nimwegen, M., Bergen, I. M. et al., Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 2008. 181:3755-3759.
Willart, M. A. and Hammad, H., Alarming dendritic cells for allergic sensitization. Allergol. Int. 2010. 59:95-103.
Hammad, H., Chieppa, M., Perros, F., Willart, M. A., Germain, R. N. and Lambrecht B. N., House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 2009. 15:410-416.
Perrigoue, J. G., Marshall, F. A. and Artis, D., On the hunt for helminths: innate immune cells in the recognition and response to helminth parasites. Cell. Microbiol. 2008. 10:1757-1764.
Deaton, A. M., Cook, P. C., De Sousa D., Phythian-Adams, A. T., Bird A. and MacDonald, A. S., A unique DNA methylation signature defines a population of IFN-γ/IL-4 double-positive T cells during helminth infection. Eur. J. Immunol. 2014. 44:1835-1841.
Fiorentino, D. F., Bond, M. W. and Mosmann, T. R., Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 1989. 170:2081-2095.
Ng, T. H. S., Britton, G. J., Hill, E. V., Verhagen, J., Burton B. R. and Wraith, D. C., Regulation of adaptive immunity; the role of interleukin-10. Front. Immunol. 2013. 4:129.
Shoemaker, J., Saraiva, M. and O'Garra, A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol. 2006. 176:3470-3479.
Motomura, Y., Kitamura, H., Hijikata, A., Matsunaga, Y., Matsumoto, K., Inoue, H., Atarashi, K. et al., The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat. Immunol. 2011. 12:450-459.
Kim, J. I., Ho, I. C., Grusby, M. J. and Glimcher, L. H. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 1999. 10:745-751.
Suzukawa, M., Morita, H., Nambu, A., Arae, K., Shimura, E., Shibui, A., Yamaguchi, S. et al., Epithelial cell-derived IL-25, but not Th17 cell-derived IL-17 or IL-17F, is crucial for murine asthma. J. Immunol. 2012. 189:3641-3652.
Pasare, C. and Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003. 299:1033-1036.
Wan, S., Xia, C. and Morel, L., IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J. Immunol. 2007. 178:271-279.
Lisbonne, M., Diem S., de Castro Keller, A., Lefort, J., Araujo, L. M., Hachem, P., Fourneau, J. M. et al., Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol. 2003. 171:1637-1641.
Akbari, O., Stock, P., Meyer, E., Kronenberg, M., Sidobre, S., Nakayama, T., Taniguchi, M. et al., Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 2003. 9:582-588.
Brigl, M., Tatituri, R. V., V., Watts, G. F. M, Bhowruth, V., Leadbetter, E. A., Barton N., Cohen N. R. et al., Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 2011. 208:1163-1177.
Yang, Y., Ochando, J., Yopp, A., Bromberg, J. S. and Ding, Y., IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation. J. Immunol. 2005. 174:2720-2729.
Krishnamoorthy, N., Oriss, T. B., Paglia, M., Fei, M., Yarlagadda, M., Vanhaesebroeck, B., Ray, A. et al., Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat. Med. 2008. 14:565-573.
Dodge, I. L., Carr, M. W., Cernadas, M. and Brenner, M. B., IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. J. Immunol. 2003. 170:4457-4464.
La Flamme, A. C. and Pearce E. J., The absence of IL-6 does not affect Th2 cell development in vivo, but does lead to impaired proliferation, IL-2 receptor expression, and B cell responses. J. Immunol. 1999. 162:5829-5837.
La Flamme, A. C., MacDonald A. S. and Pearce E. J., Role of IL-6 in directing the initial immune response to schistosome eggs. J. Immunol. 2000. 164:2419-2426.
Yokota-Nakatsuma, A., Takeuchi, H., Ohoka, Y., Kato, C., Song, S-Y., Hoshino, T., Yagita, H. et al., Retinoic acid prevents mesenteric lymph node dendritic cells from inducing IL-13-producing inflammatory Th2 cells. Mucosal Immunol. 2013. 7:786-801.
Wiethe, C., Debus, A., Mohrs, M., Steinkasserer, A., Lutz, M. and Gessner, A., Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection. J. Immunol. 2008. 180:4371-4381.
Eddahri, F., Oldenhove, G., Denanglaire, S., Urbain, J., Leo, O. and Andris, F., CD4+ CD25+ regulatory T cells control the magnitude of T-dependent humoral immune responses to exogenous antigens. Eur. J. Immunol. 2006. 36:855-863.
