Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs

Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and ef...

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Main Authors:	Gmyrek, Grzegorz B., Akilesh, Holly M., Graham, Daniel B., Fuchs, Anja, Yang, Lihua, Miller, Mark J., Sandoval, Gabriel J., Sheehan, Kathleen C. F., Schreiber, Robert D., Diamond, Michael S., Swat, Wojciech
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796521/

id	pubmed-3796521
recordtype	oai_dc
spelling	pubmed-37965212013-10-23 Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs Gmyrek, Grzegorz B. Akilesh, Holly M. Graham, Daniel B. Fuchs, Anja Yang, Lihua Miller, Mark J. Sandoval, Gabriel J. Sheehan, Kathleen C. F. Schreiber, Robert D. Diamond, Michael S. Swat, Wojciech Research Article Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8+ T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8+ T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8+ T cell responses. Public Library of Science 2013-10-14 /pmc/articles/PMC3796521/ /pubmed/24155889 http://dx.doi.org/10.1371/journal.pone.0076145 Text en © 2013 Gmyrek et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Gmyrek, Grzegorz B. Akilesh, Holly M. Graham, Daniel B. Fuchs, Anja Yang, Lihua Miller, Mark J. Sandoval, Gabriel J. Sheehan, Kathleen C. F. Schreiber, Robert D. Diamond, Michael S. Swat, Wojciech
spellingShingle	Gmyrek, Grzegorz B. Akilesh, Holly M. Graham, Daniel B. Fuchs, Anja Yang, Lihua Miller, Mark J. Sandoval, Gabriel J. Sheehan, Kathleen C. F. Schreiber, Robert D. Diamond, Michael S. Swat, Wojciech Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
author_facet	Gmyrek, Grzegorz B. Akilesh, Holly M. Graham, Daniel B. Fuchs, Anja Yang, Lihua Miller, Mark J. Sandoval, Gabriel J. Sheehan, Kathleen C. F. Schreiber, Robert D. Diamond, Michael S. Swat, Wojciech
author_sort	Gmyrek, Grzegorz B.
title	Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
title_short	Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
title_full	Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
title_fullStr	Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
title_full_unstemmed	Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs
title_sort	loss of dap12 and fcrγ drives exaggerated il-12 production and cd8+ t cell response by ccr2+ mo-dcs
description	Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8+ T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8+ T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8+ T cell responses.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796521/
_version_	1612018208788709376

Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs

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