Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

S. Dallari; M. Macal; M. E. Loureiro; Y. Jo; L. Swanson; C. Hesser; P. Ghosh; E. I. Zuniga

doi:10.1038/ncomms14830

journal article Open Access Apr 03, 2017

Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

S. Dallari M. Macal M. E. Loureiro Y. Jo L. Swanson C. Hesser P. Ghosh E. I. Zuniga

Nature Communications Vol. 8 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/ncomms14830

Abstract

AbstractPlasmacytoid dendritic cells (pDC) are type I interferon-producing cells with critical functions in a number of human illnesses; however, their molecular regulation is incompletely understood. Here we show the role of Src family kinases (SFK) in mouse and human pDCs. pDCs express Fyn and Lyn and their activating residues are phosphorylated both before and after Toll-like receptor (TLR) stimulation. Fyn or Lyn genetic ablation as well as treatment with SFK inhibitors ablate pDC (but not conventional DC) responses bothin vitroandin vivo. Inhibition of SFK activity not only alters TLR-ligand localization and inhibits downstream signalling events, but, independent ofex-vivoTLR stimulation, also affects constitutive phosphorylation of BCAP, an adaptor protein bridging PI3K and TLR pathways. Our data identify Fyn and Lyn as important factors that promote pDC responses, describe the mechanisms involved and highlight a tonic SFK-mediated signalling that precedes pathogen encounter, raising the possibility that small molecules targeting SFKs could modulate pDC responses in human diseases.

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References

64

[1]

Kawai, T. & Akira, S. Antiviral signaling through pattern recognition receptors. J. Biochem. 141, 137–145 (2007). 10.1093/jb/mvm032

[2]

Blasius, A. L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305–315 (2010). 10.1016/j.immuni.2010.03.012

[3]

Mcnab, F., Mayer-barber, K., Sher, A., Wack, A. & Garra, A. O. Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 (2015). 10.1038/nri3787

[4]

Regulation of type I interferon responses

Lionel B. Ivashkiv, Laura T. Donlin

Nature Reviews Immunology 2014 10.1038/nri3581

[5]

Type I interferons in anticancer immunity

Laurence Zitvogel, Lorenzo Galluzzi, Oliver Kepp et al.

Nature Reviews Immunology 2015 10.1038/nri3845

[6]

Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006). 10.1016/j.immuni.2006.08.010

[7]

Huang, X., Dorta-Estremera, S., Yao, Y., Shen, N. & Cao, W. Predominant role of plasmacytoid dendritic cells in stimulating systemic autoimmunity. Front. Immunol. 6, 1–6 (2015). 10.3389/fimmu.2015.00526

[8]

Teijaro, J. R. et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340, 207–211 (2013). 10.1126/science.1235214

[9]

Wilson, E. B. et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340, 202–207 (2013). 10.1126/science.1235208

[10]

Sandler, N. G. et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511, 601–605 (2014). 10.1038/nature13554

[11]

Zuniga, E. I., Macal, M., Lewis, G. M. & Harker, J. A. Innate and adaptive immune regulation during chronic viral infections. Annu. Rev. Virol. 2, 573–597 (2015). 10.1146/annurev-virology-100114-055226

[12]

The multifaceted biology of plasmacytoid dendritic cells

Melissa Swiecki, Marco Colonna

Nature Reviews Immunology 2015 10.1038/nri3865

[13]

Reizis, B., Bunin, A., Ghosh, H. S., Lewis, K. L. & Sisirak, V. Plasmacytoid dendritic cells: recent progress and open questions. Annu. Rev. Immunol. 29, 163–183 (2011). 10.1146/annurev-immunol-031210-101345

[14]

Gilliet, M., Cao, W. & Liu, Y.-J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594–606 (2008). 10.1038/nri2358

[15]

Izaguirre, A. et al. Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J. Leukoc. Biol. 74, 1125–1138 (2003). 10.1189/jlb.0603255

[16]

Kerkmann, M. et al. Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J. Immunol. 170, 4465–4474 (2003). 10.4049/jimmunol.170.9.4465

[17]

Honda, K. et al. Spatiotemporal regulation of MyD88 – IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005). 10.1038/nature03547

[18]

Cao, W. & Bover, L. Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells. Immunol. Rev. 234, 163–176 (2010). 10.1111/j.0105-2896.2009.00867.x

[19]

Korade-Mirnics, Z. & Corey, S. J. Src kinase-mediated signaling in leukocytes. J. Leukoc. Biol. 68, 603–613 (2000). 10.1189/jlb.68.5.603

[20]

Lowell, C. A. Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb. Perspect. Biol. 3, a002352 (2011). 10.1101/cshperspect.a002352

[21]

Sanjuan, M. A. et al. CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion. J. Cell Biol. 172, 1057–1068 (2006). 10.1083/jcb.200508058

[22]

Fujita, H. et al. The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA. Eur. J. Immunol. 43, 93–103 (2013). 10.1002/eji.201242699

[23]

Cao, W. et al. BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells. PLoS Biol. 5, e248 (2007). 10.1371/journal.pbio.0050248

[24]

Dzionek, A. et al. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J. Exp. Med. 194, 1823–1834 (2001). 10.1084/jem.194.12.1823

[25]

Röck, J. et al. CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. Eur. J. Immunol. 37, 3564–3575 (2007). 10.1002/eji.200737711

[26]

Maeda, T. et al. A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma. Int. J. Hematol. 81, 148–154 (2005). 10.1532/ijh97.04116

[27]

Yu, C. C., Yen, T. S., Lowell, C. A. & DeFranco, A. L. Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. Curr. Biol. 11, 34–38 (2001). 10.1016/s0960-9822(00)00024-5

[28]

Lamagna, C., Scapini, P., van Ziffle, J. A., DeFranco, A. L. & Lowell, C. A. Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc. Natl Acad. Sci. USA 110, E3311–E3320 (2013). 10.1073/pnas.1300617110

[29]

Interferon α/β and Interleukin 12 Responses to Viral Infections

Marc Dalod, Thais P. Salazar-Mather, Lene Malmgaard et al.

The Journal of Experimental Medicine 2002 10.1084/jem.20011672

[30]

Swiecki, M., Gilfillan, S., Vermi, W., Wang, Y. & Colonna, M. Plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral NK and CD8(+) T cell accrual. Immunity 33, 955–966 (2010). 10.1016/j.immuni.2010.11.020

[31]

IRF-7 is the master regulator of type-I interferon-dependent immune responses

Kenya Honda, Hideyuki Yanai, Hideo Negishi et al.

Nature 2005 10.1038/nature03464

[32]

Asselin-Paturel, C. et al. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J. Exp. Med. 201, 1157–1167 (2005). 10.1084/jem.20041930

[33]

Guiducci, C. et al. PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation. J. Exp. Med. 205, 315–322 (2008). 10.1084/jem.20070763

[34]

Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat. Immunol. 9, 1157–1164 (2008). 10.1038/ni.1645

[35]

Troutman, T. D. et al. Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc. Natl Acad. Sci. USA 109, 273–278 (2012). 10.1073/pnas.1118579109

[36]

Ni, M. et al. B-cell adaptor for PI3K (BCAP) negatively regulates toll-like receptor signaling through activation of PI3K. Proc. Natl Acad. Sci. USA 109, 267–272 (2012). 10.1073/pnas.1111957108

[37]

Okada, T., Maeda, A., Iwamatsu, A., Gotoh, K. & Kurosaki, T. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 13, 817–827 (2000). 10.1016/s1074-7613(00)00079-0

[38]

Inabe, K. & Kurosaki, T. Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement. Blood 99, 584–589 (2002). 10.1182/blood.v99.2.584

[39]

Guiducci, C. et al. Properties regulating the nature of the plasmacytoid dendritic cell response to toll-like receptor 9 activation. J. Exp. Med. 203, 1999–2008 (2006). 10.1084/jem.20060401

[40]

Sasai, M., Linehan, M. M. & Iwasaki, A. Bifurcation of toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530–1534 (2010). 10.1126/science.1187029

[41]

Kimura, S. et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106, 3948–3954 (2005). 10.1182/blood-2005-06-2209

[42]

Kantarjian, H. et al. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer 116, 2665–2672 (2010). 10.1002/cncr.25079

[43]

Portnow, J. et al. A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas. Eur. J. Cancer 49, 1634–1640 (2013). 10.1016/j.ejca.2013.01.001

[44]

Vermi, W., Soncini, M., Melocchi, L., Sozzani, S. & Facchetti, F. Plasmacytoid dendritic cells and cancer. J. Leukoc. Biol. 90, 681–690 (2011). 10.1189/jlb.0411190

[45]

Gregorio, J. et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J. Exp. Med. 207, 2921–2930 (2010). 10.1084/jem.20101102

[46]

Niiro, H. & Clark, E. A. Regulation of B-cell fate by antigen-receptor signals. Nat. Rev. Immunol. 2, 945–956 (2002). 10.1038/nri955

[47]

Smith, K. G. C., Tarlinton, D. M., Doody, G. M., Hibbs, M. L. & Fearon, D. T. Inhibition of the B cell by CD22: a requirement for Lyn. J. Exp. Med. 187, 807–811 (1998). 10.1084/jem.187.5.807

[48]

Positive and Negative Regulation of Mast Cell Activation by Lyn via the FcεRI

Wenbin Xiao, Hajime Nishimoto, Hong Hong et al.

The Journal of Immunology 2005 10.4049/jimmunol.175.10.6885

[49]

Reinecke, J. & Caplan, S. Endocytosis and the Src family of non-receptor tyrosine kinases. Biomol. Concepts 5, 143–155 (2014). 10.1515/bmc-2014-0003

[50]

Sato, I. et al. Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain. J. Cell Sci. 122, 965–975 (2009). 10.1242/jcs.034843

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Published: Apr 03, 2017
Vol/Issue: 8(1)
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Cite This Article

S. Dallari, M. Macal, M. E. Loureiro, et al. (2017). Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses. Nature Communications, 8(1). https://doi.org/10.1038/ncomms14830

Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

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