Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation

Casper Marsman, Fanny Lafouresse, Yang Liao, Tracey M. Baldwin, Lisa A. Mielke, Yifang Hu, Matthias Mack, Paul J. Hertzog, Carolyn A. de Graaf, Wei Shi, Joanna R. Groom

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the downstream effectors of type I IFN signaling that amplify autoimmune responses. Here, we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation, conventional type 1 and type 2 DCs (cDC1 and cDC2, respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10+ and CXCL10 populations could be distinguished. CXCL9 expression was induced in all cDC1s, in half of the cDC2 but not by pDCs. The requirement for IFNAR signaling for chemokine reporter expression was interrogated by receptor blocking and deficiency and shown to be critical for CXCR3 ligand expression in Flt3-ligand-derived DCs. Chemokine-producing potential was not concordant with the previously identified markers of pDC heterogeneity. Finally, we show that CXCL10+ and CXCL10 populations are transcriptionally distinct, expressing unique transcriptional regulators, IFN signaling molecules, chemokines, cytokines, and cell surface markers. This work highlights CXCL10 as a downstream effector of type I IFN signaling and suggests a division of labor in pDCs subtypes that likely impacts their function as effectors of viral responses and as drivers of inflammation.

Original languageEnglish
Pages (from-to)1083-1094
Number of pages12
JournalImmunology and Cell Biology
Volume96
Issue number10
DOIs
Publication statusPublished - 1 Nov 2018
Externally publishedYes

Keywords

  • Chemokine
  • conventional DC
  • CXCR3
  • IFNAR1
  • IMQ
  • plasmacytoid DC
  • SLE
  • TLR7
  • type 1 IFN

Cite this

Marsman, C., Lafouresse, F., Liao, Y., Baldwin, T. M., Mielke, L. A., Hu, Y., ... Groom, J. R. (2018). Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation. Immunology and Cell Biology, 96(10), 1083-1094. https://doi.org/10.1111/imcb.12173
Marsman, Casper ; Lafouresse, Fanny ; Liao, Yang ; Baldwin, Tracey M. ; Mielke, Lisa A. ; Hu, Yifang ; Mack, Matthias ; Hertzog, Paul J. ; de Graaf, Carolyn A. ; Shi, Wei ; Groom, Joanna R. / Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation. In: Immunology and Cell Biology. 2018 ; Vol. 96, No. 10. pp. 1083-1094.
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Marsman, C, Lafouresse, F, Liao, Y, Baldwin, TM, Mielke, LA, Hu, Y, Mack, M, Hertzog, PJ, de Graaf, CA, Shi, W & Groom, JR 2018, 'Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation', Immunology and Cell Biology, vol. 96, no. 10, pp. 1083-1094. https://doi.org/10.1111/imcb.12173

Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation. / Marsman, Casper; Lafouresse, Fanny; Liao, Yang; Baldwin, Tracey M.; Mielke, Lisa A.; Hu, Yifang; Mack, Matthias; Hertzog, Paul J.; de Graaf, Carolyn A.; Shi, Wei; Groom, Joanna R.

In: Immunology and Cell Biology, Vol. 96, No. 10, 01.11.2018, p. 1083-1094.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Marsman, Casper

AU - Lafouresse, Fanny

AU - Liao, Yang

AU - Baldwin, Tracey M.

AU - Mielke, Lisa A.

AU - Hu, Yifang

AU - Mack, Matthias

AU - Hertzog, Paul J.

AU - de Graaf, Carolyn A.

AU - Shi, Wei

AU - Groom, Joanna R.

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AB - Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the downstream effectors of type I IFN signaling that amplify autoimmune responses. Here, we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation, conventional type 1 and type 2 DCs (cDC1 and cDC2, respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10+ and CXCL10− populations could be distinguished. CXCL9 expression was induced in all cDC1s, in half of the cDC2 but not by pDCs. The requirement for IFNAR signaling for chemokine reporter expression was interrogated by receptor blocking and deficiency and shown to be critical for CXCR3 ligand expression in Flt3-ligand-derived DCs. Chemokine-producing potential was not concordant with the previously identified markers of pDC heterogeneity. Finally, we show that CXCL10+ and CXCL10− populations are transcriptionally distinct, expressing unique transcriptional regulators, IFN signaling molecules, chemokines, cytokines, and cell surface markers. This work highlights CXCL10 as a downstream effector of type I IFN signaling and suggests a division of labor in pDCs subtypes that likely impacts their function as effectors of viral responses and as drivers of inflammation.

KW - Chemokine

KW - conventional DC

KW - CXCR3

KW - IFNAR1

KW - IMQ

KW - plasmacytoid DC

KW - SLE

KW - TLR7

KW - type 1 IFN

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