Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice

被引：44

作者：

Billiard, Fabienne ^{[1
]}

Lobry, Camille ^{[2
]}

Darrasse-Jeze, Guillaume ^{[4
]}

Waite, Janelle ^{[1
]}

Liu, Xia ^{[1
]}

Mouquet, Hugo ^{[4
]}

DaNave, Amanda ^{[1
]}

Tait, Michelle ^{[1
]}

Idoyaga, Juliana ^{[5
]}

Leboeuf, Marylene ^{[6
]}

Kyratsous, Christos A. ^{[1
]}

Burton, Jacquelynn ^{[1
]}

Kalter, Julie ^{[1
]}

Klinakis, Apostolos ^{[7
]}

Zhang, Wen ^{[1
]}

Thurston, Gavin ^{[1
]}

Merad, Miriam ^{[6
]}

Steinman, Ralph M. ^{[5
]}

Murphy, Andrew J. ^{[1
]}

Yancopoulos, George D. ^{[1
]}

Aifantis, Iannis ^{[2
,3
]}

Skokos, Dimitris ^{[1
]}

机构：

[1] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA

[2] NYU, Dept Pathol, New York, NY 10016 USA

[3] NYU, Howard Hughes Med Inst, New York, NY 10016 USA

[4] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA

[5] Rockefeller Univ, Lab Cellular Physiol & Immunol, New York, NY 10065 USA

[6] Mt Sinai Sch Med, Inst Immunol, Dept Med, Dept Genes & Cell Med, New York, NY 10029 USA

[7] Acad Athens, Biomed Res Fdn, Athens 11527, Greece

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2012年 / 209卷 / 05期

关键词：

REGULATORY T-CELLS; DELTA-LIKE; 4; POSITIVE SELECTION; NOD MICE; NOTCH; HOMEOSTASIS; EXPRESSION; LIGAND; DIFFERENTIATION; PRECURSORS;

D O I：

10.1084/jem.20111615

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Delta-like ligand 4 (Dll4)-Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4-Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4(+)CD25(+)FoxP3(+) regulatory T cells (T-reg cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural T-reg cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4(-)CD8(-)c-kit(+)CD44(+)CD25(-) (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4(+) T cells into T-reg cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of T-reg cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti-Dll4 treatment fully prevents type 1 diabetes (T1D) via a T-reg cell-mediated mechanism and inhibits CD8(+) T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased T-reg cell numbers in the pancreas-draining lymph nodes. These results identify Dll4-Notch as a novel Flt3-alternative pathway important for regulating tDC-mediated T-reg cell homeostasis and autoimmunity.

引用

页码：1011 / 1028

页数：18

共 70 条

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