BACKGROUND: Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. METHODS AND RESULTS: Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4(-/flox) bone marrow transplanted into Ldlr(-/-) mice. Compared with control Ldlr(-/-) chimeric mice, CD11c-Cre × Tcf4(-/flox) mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr(-/-) mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100-specific CD4(+) T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell-derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4(+) T cell-depleted animals. CONCLUSIONS: This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity.

MHC Class II-Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity / A. P., Sage; D., Murphy; Maffia, Pasquale; L. M., Masters; S. R., Sabir; L. L., Baker; H., Cambrook; A. J., Finigan; H., Ait Oufella; Grassia, Gianluca; J. E., Harrison; B., Ludewig; W., Reith; G. K., Hansson; B., Reizis; S., Hugues; Z., Mallat. - In: CIRCULATION. - ISSN 0009-7322. - 130:16(2014), pp. 1363-1373. [10.1161/CIRCULATIONAHA.114.011090]

MHC Class II-Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity

MAFFIA, PASQUALE;GRASSIA, GIANLUCA;
2014

Abstract

BACKGROUND: Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. METHODS AND RESULTS: Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4(-/flox) bone marrow transplanted into Ldlr(-/-) mice. Compared with control Ldlr(-/-) chimeric mice, CD11c-Cre × Tcf4(-/flox) mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr(-/-) mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100-specific CD4(+) T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell-derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4(+) T cell-depleted animals. CONCLUSIONS: This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity.
2014
MHC Class II-Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity / A. P., Sage; D., Murphy; Maffia, Pasquale; L. M., Masters; S. R., Sabir; L. L., Baker; H., Cambrook; A. J., Finigan; H., Ait Oufella; Grassia, Gianluca; J. E., Harrison; B., Ludewig; W., Reith; G. K., Hansson; B., Reizis; S., Hugues; Z., Mallat. - In: CIRCULATION. - ISSN 0009-7322. - 130:16(2014), pp. 1363-1373. [10.1161/CIRCULATIONAHA.114.011090]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/588998
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 80
  • ???jsp.display-item.citation.isi??? 70
social impact