Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis
Abstract
:1. Introduction
2. Results
2.1. mDCs Isolated from Untreated- and IFNb-Treated MS Patients Markedly Differ in Their Ability to Become Tolerogenic in Response to IL-27 Stimulation
2.2. IL-27 Induces PDL2 and IDO1 in Human Ex Vivo mDCs
2.3. mDCs Isolated from Untreated Patients with MS Show an Altered Gene Expression Response to IL-27
2.4. Circulating mDCs Exibit Different Gene Expression Signature Regarding Disease and Treatment Status
3. Discussion
4. Methods
4.1. Patients
4.2. Standard Protocol Approvals, Registrations, and Patient Consents
4.3. mDC and Naïve T Cell Isolation
4.4. In Vitro DC Stimulation and Culture
4.5. RNA Analysis
4.6. Flow Cytometry Analysis
4.7. Measuring Supernatant Cytokines
4.8. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Hauser, S.L. Multiple lessons for multiple sclerosis. N. Engl. J. Med. 2008, 359, 1838–1841. [Google Scholar] [CrossRef] [PubMed]
- Frisullo, G.; Nociti, V.; Iorio, R.; Patanella, A.K.; Marti, A.; Caggiula, M.; Mirabella, M.; Tonali, P.A.; Batocchi, A.P. IL17 and IFNgamma production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis. Cytokine 2008, 44, 22–25. [Google Scholar] [CrossRef] [PubMed]
- Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 2008, 172, 146–155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sospedra, M.; Martin, R. Antigen-specific therapies in multiple sclerosis. Int. Rev. Immunol. 2005, 24, 393–413. [Google Scholar] [CrossRef] [PubMed]
- Pashenkov, M.; Huang, Y.M.; Kostulas, V.; Haglund, M.; Soderstrom, M.; Link, H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001, 124, 480–492. [Google Scholar] [CrossRef] [Green Version]
- Lakey, R.L.; Morgan, T.G.; Rowan, A.D.; Isaacs, J.D.; Cawston, T.E.; Hilkens, C.M. A novel paradigm for dendritic cells as effectors of cartilage destruction. Rheumatology 2009, 48, 502–507. [Google Scholar] [CrossRef] [Green Version]
- Ransohoff, R.M.; Brown, M.A. Innate immunity in the central nervous system. J. Clin. Investig. 2012, 122, 1164–1171. [Google Scholar] [CrossRef]
- Banchereau, J.; Steinman, R.M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252. [Google Scholar] [CrossRef]
- Bailey, S.L.; Schreiner, B.; McMahon, E.J.; Miller, S.D. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat. Immunol. 2007, 8, 172–180. [Google Scholar] [CrossRef]
- Farias, A.S.; Spagnol, G.S.; Bordeaux-Rego, P.; Oliveira, C.O.; Fontana, A.G.; de Paula, R.F.; Santos, M.P.; Pradella, F.; Moraes, A.S.; Oliveira, E.C.; et al. Vitamin D3 induces IDO+ tolerogenic DCs and enhances Treg, reducing the severity of EAE. CNS Neurosci. Ther. 2013, 19, 269–277. [Google Scholar] [CrossRef]
- Raker, V.K.; Domogalla, M.P.; Steinbrink, K. Tolerogenic Dendritic Cells for Regulatory T Cell Induction in Man. Front. Immunol. 2015, 6, 569. [Google Scholar] [CrossRef] [Green Version]
- Hunter, C.A.; Kastelein, R. Interleukin-27: Balancing protective and pathological immunity. Immunity 2012, 37, 960–969. [Google Scholar] [CrossRef] [Green Version]
- Murugaiyan, G.; Mittal, A.; Weiner, H.L. Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-gamma limits IL-17-mediated autoimmune inflammation. Proc. Natl. Acad. Sci. USA 2010, 107, 11495–11500. [Google Scholar] [CrossRef] [Green Version]
- Zhu, C.; Sakuishi, K.; Xiao, S.; Sun, Z.; Zaghouani, S.; Gu, G.; Wang, C.; Tan, D.J.; Wu, C.; Rangachari, M.; et al. An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat. Commun. 2015, 6, 6072. [Google Scholar] [CrossRef] [Green Version]
- Thome, R.; Moore, J.N.; Mari, E.R.; Rasouli, J.; Hwang, D.; Yoshimura, S.; Ciric, B.; Zhang, G.X.; Rostami, A.M. Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells. Front. Immunol. 2017, 8, 1392. [Google Scholar] [CrossRef]
- Sweeney, C.M.; Lonergan, R.; Basdeo, S.A.; Kinsella, K.; Dungan, L.S.; Higgins, S.C.; Kelly, P.J.; Costelloe, L.; Tubridy, N.; Mills, K.H.; et al. IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav. Immun. 2011, 25, 1170–1181. [Google Scholar] [CrossRef]
- Von Bubnoff, D.; Scheler, M.; Wilms, H.; Fimmers, R.; Bieber, T. Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli. J. Immunol. 2011, 186, 6701–6709. [Google Scholar] [CrossRef] [Green Version]
- Piccioli, D.; Tavarini, S.; Borgogni, E.; Steri, V.; Nuti, S.; Sammicheli, C.; Bardelli, M.; Montagna, D.; Locatelli, F.; Wack, A. Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets. Blood 2007, 109, 5371–5379. [Google Scholar] [CrossRef] [Green Version]
- Han, T.H.; Jin, P.; Ren, J.; Slezak, S.; Marincola, F.M.; Stroncek, D.F. Evaluation of 3 clinical dendritic cell maturation protocols containing lipopolysaccharide and interferon-gamma. J. Immunother. 2009, 32, 399–407. [Google Scholar] [CrossRef] [Green Version]
- Stumhofer, J.S.; Silver, J.S.; Laurence, A.; Porrett, P.M.; Harris, T.H.; Turka, L.A.; Ernst, M.; Saris, C.J.; O’Shea, J.J.; Hunter, C.A. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 2007, 8, 1363–1371. [Google Scholar] [CrossRef]
- Hundeshagen, A.; Hecker, M.; Paap, B.K.; Angerstein, C.; Kandulski, O.; Fatum, C.; Hartmann, C.; Koczan, D.; Thiesen, H.J.; Zettl, U.K. Elevated type I interferon-like activity in a subset of multiple sclerosis patients: Molecular basis and clinical relevance. J. Neuroinflamm. 2012, 9, 140. [Google Scholar] [CrossRef] [Green Version]
- Latchman, Y.; Wood, C.R.; Chernova, T.; Chaudhary, D.; Borde, M.; Chernova, I.; Iwai, Y.; Long, A.J.; Brown, J.A.; Nunes, R.; et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2001, 2, 261–268. [Google Scholar] [CrossRef] [PubMed]
- Brown, J.A.; Dorfman, D.M.; Ma, F.R.; Sullivan, E.L.; Munoz, O.; Wood, C.R.; Greenfield, E.A.; Freeman, G.J. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 2003, 170, 1257–1266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nishimura, H.; Honjo, T. PD-1: An inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001, 22, 265–268. [Google Scholar] [CrossRef] [PubMed]
- Hirahara, K.; Ghoreschi, K.; Yang, X.P.; Takahashi, H.; Laurence, A.; Vahedi, G.; Sciume, G.; Hall, A.O.; Dupont, C.D.; Francisco, L.M.; et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 2012, 36, 1017–1030. [Google Scholar] [CrossRef] [Green Version]
- Pittet, C.L.; Newcombe, J.; Prat, A.; Arbour, N. Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis. J. Neuroinflamm. 2011, 8, 155. [Google Scholar] [CrossRef] [Green Version]
- Schwarcz, R.; Bruno, J.P.; Muchowski, P.J.; Wu, H.Q. Kynurenines in the mammalian brain: When physiology meets pathology. Nat. Rev. Neurosci. 2012, 13, 465–477. [Google Scholar] [CrossRef]
- Merad, M.; Manz, M.G. Dendritic cell homeostasis. Blood 2009, 113, 3418–3427. [Google Scholar] [CrossRef] [Green Version]
- Sallusto, F.; Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 1994, 179, 1109–1118. [Google Scholar] [CrossRef] [Green Version]
- van de Laar, L.; Coffer, P.J.; Woltman, A.M. Regulation of dendritic cell development by GM-CSF: Molecular control and implications for immune homeostasis and therapy. Blood 2012, 119, 3383–3393. [Google Scholar] [CrossRef]
- Laouar, Y.; Welte, T.; Fu, X.Y.; Flavell, R.A. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 2003, 19, 903–912. [Google Scholar] [CrossRef] [Green Version]
- Sun, Y.; Chin, Y.E.; Weisiger, E.; Malter, C.; Tawara, I.; Toubai, T.; Gatza, E.; Mascagni, P.; Dinarello, C.A.; Reddy, P. Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. J. Immunol. 2009, 182, 5899–5903. [Google Scholar] [CrossRef] [Green Version]
- Nefedova, Y.; Cheng, P.; Gilkes, D.; Blaskovich, M.; Beg, A.A.; Sebti, S.M.; Gabrilovich, D.I. Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J. Immunol. 2005, 175, 4338–4346. [Google Scholar] [CrossRef] [Green Version]
- Hoentjen, F.; Sartor, R.B.; Ozaki, M.; Jobin, C. STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood 2005, 105, 689–696. [Google Scholar] [CrossRef] [Green Version]
- Huber, J.P.; Farrar, J.D. Regulation of effector and memory T-cell functions by type I interferon. Immunology 2011, 132, 466–474. [Google Scholar] [CrossRef] [PubMed]
- Gallucci, S.; Lolkema, M.; Matzinger, P. Natural adjuvants: Endogenous activators of dendritic cells. Nat. Med. 1999, 5, 1249–1255. [Google Scholar] [CrossRef]
- Steinman, R.M.; Hawiger, D.; Liu, K.; Bonifaz, L.; Bonnyay, D.; Mahnke, K.; Iyoda, T.; Ravetch, J.; Dhodapkar, M.; Inaba, K.; et al. Dendritic cell function in vivo during the steady state: A role in peripheral tolerance. Ann. N.Y. Acad. Sci. 2003, 987, 15–25. [Google Scholar] [CrossRef]
- Lee, K.H.; Holdorf, A.D.; Dustin, M.L.; Chan, A.C.; Allen, P.M.; Shaw, A.S. T cell receptor signaling precedes immunological synapse formation. Science 2002, 295, 1539–1542. [Google Scholar] [CrossRef] [Green Version]
- Tseng, S.Y.; Waite, J.C.; Liu, M.; Vardhana, S.; Dustin, M.L. T cell-dendritic cell immunological synapses contain TCR-dependent CD28-CD80 clusters that recruit protein kinase C theta. J. Immunol. 2008, 181, 4852–4863. [Google Scholar] [CrossRef] [Green Version]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
von Glehn, F.; Pochet, N.; Thapa, B.; Raheja, R.; Mazzola, M.A.; Jangi, S.; Beynon, V.; Huang, J.; Farias, A.S.; Paul, A.; et al. Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis. Int. J. Mol. Sci. 2023, 24, 8000. https://doi.org/10.3390/ijms24098000
von Glehn F, Pochet N, Thapa B, Raheja R, Mazzola MA, Jangi S, Beynon V, Huang J, Farias AS, Paul A, et al. Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis. International Journal of Molecular Sciences. 2023; 24(9):8000. https://doi.org/10.3390/ijms24098000
Chicago/Turabian Stylevon Glehn, Felipe, Nathalie Pochet, Bibek Thapa, Radhika Raheja, Maria A. Mazzola, Sushrut Jangi, Vanessa Beynon, Junning Huang, Alessandro S. Farias, Anu Paul, and et al. 2023. "Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis" International Journal of Molecular Sciences 24, no. 9: 8000. https://doi.org/10.3390/ijms24098000