A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4+ T cells and is defective in Crohn′s disease patients

被引：17

作者：

Ahlers, Jonas ^{[1
,15
]}

Mantei, Andrej ^{[2
]}

Lozza, Laura ^{[3
]}

Staeber, Manuela ^{[4
]}

Heinrich, Frederik ^{[5
]}

Bacher, Petra ^{[6
,7
,8
]}

Hohnstein, Thordis ^{[9
]}

Menzel, Lutz ^{[10
]}

Yuez, Simge G. ^{[6
,7
]}

Alvarez-Simon, Daniel ^{[6
,7
]}

Bickenbach, Anne Rieke ^{[6
,7
]}

Weidinger, Carl ^{[11
]}

Mockel-Tenbrinck, Nadine ^{[12
]}

Kuehl, Anja A. ^{[13
]}

Siegmund, Britta ^{[11
]}

Maul, Jochen ^{[11
,14
]}

Neumann, Christian ^{[9
]}

Scheffold, Alexander ^{[6
,7
]}

机构：

[1] Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany

[2] Charite Vivantes GmbH, Lab Berlin, Berlin, Germany

[3] Precis Med GmbH, Cell Biol, Berlin, Germany

[4] Max Plack Inst Infect Biol, Cent Lab Serv, Berlin, Germany

[5] Leibniz Assoc, German Rheumatism Res Ctr DRFZ Berlin, Berlin, Germany

[6] Christian Albrechts Univ Kiel, Inst Immunol, Schleswig Holstein, Germany

[7] UKSH Schleswig Holstein, Schleswig Holstein, Germany

[8] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Schleswig Holst, Germany

[9] Charite Univ Med Berlin, Dept Microbiol Infect Dis & Immunol, Berlin, Germany

[10] Max Delbruck Ctr Mol Med, Translat Tumor Immunol, Berlin, Germany

[11] Charite Univ Med Berlin, Dept Gastroenterol Infect Dis & Rheumatol, Campus Benjamin Franklin, Berlin, Germany

[12] Miltenyi Biotec BV & Co KG, Bergisch Gladbach, Nordrhein Westf, Germany

[13] Charite Univ Med Berlin, iPATH, Campus Benjamin Franklin, Berlin, Germany

[14] Gastroenterol Bayer Pl, Berlin, Germany

[15] Sanofi Aventis Deutschland GmbH, Sanofi Pasteur, Berlin, Germany

来源：

MUCOSAL IMMUNOLOGY | 2022年 / 15卷 / 03期

关键词：

CUTTING EDGE; TH1; CELLS; TRANSCRIPTION FACTOR; OPPOSING ROLES; IFN-ALPHA; TGF-BETA; C-MAF; INTERLEUKIN-10; STAT3; NOTCH;

D O I：

10.1038/s41385-022-00487-x

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4(+) T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4(+) T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naive and major effector CD4(+) T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4(+) T cells from Crohn's disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3-Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4(+) T cells, which is defective in IBD and thus may represent an attractive therapeutic target.

引用

页码：480 / 490

页数：11