DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

被引：179

作者：

Jabara, Haifa H. ^{[1
,2
]}

McDonald, Douglas R. ^{[1
,2
]}

Janssen, Erin ^{[1
,2
]}

Massaad, Michel J. ^{[1
,2
]}

Ramesh, Narayanaswamy ^{[1
,2
]}

Borzutzky, Arturo ^{[1
,2
]}

Rauter, Ingrid ^{[1
,2
]}

Benson, Halli ^{[1
,2
]}

Schneider, Lynda ^{[1
,2
]}

Baxi, Sachin ^{[1
,2
]}

Recher, Mike ^{[1
,2
]}

Notarangelo, Luigi D. ^{[1
,2
]}

Wakim, Rima ^{[3
]}

Dbaibo, Ghassan ^{[3
]}

Dasouki, Majed ^{[4
,5
]}

Al-Herz, Waleed ^{[6
]}

Barlan, Isil ^{[7
]}

Baris, Safa ^{[7
]}

Kutukculer, Necil ^{[8
]}

Ochs, Hans D. ^{[9
]}

Plebani, Alessandro ^{[10
,11
]}

Kanariou, Maria ^{[12
]}

Lefranc, Gerard ^{[13
]}

Reisli, Ismail ^{[14
]}

Fitzgerald, Katherine A. ^{[15
]}

Golenbock, Douglas ^{[15
]}

Manis, John ^{[16
]}

Keles, Sevgi ^{[14
,17
,18
]}

Ceja, Reuben ^{[17
,18
]}

Chatila, Talal A. ^{[17
,18
]}

Geha, Raif S. ^{[1
,2
]}

机构：

[1] Harvard Univ, Childrens Hosp, Sch Med, Div Immunol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Amer Univ Beirut, Beirut, Lebanon

[4] Univ Kansas, Med Ctr, Dept Pediat, Div Genet Endocrinol & Metab, Kansas City, KS 66103 USA

[5] Univ Kansas, Med Ctr, Dept Internal Med, Div Genet Endocrinol & Metab, Kansas City, KS 66103 USA

[6] Al Sabah Hosp, Allergy & Clin Immunol Unit, Dept Pediat, Kuwait, Kuwait

[7] Marmara Univ, Div Pediat Allergy & Immunol, Istanbul, Turkey

[8] Ege Univ, Dept Pediat Immunol, Izmir, Turkey

[9] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[10] Univ Brescia, Pediat Clin, Brescia, Italy

[11] Univ Brescia, Angelo Nocivelli Inst Mol Med, Brescia, Italy

[12] Agia Sophia Childrens Hosp, Athens, Greece

[13] Univ Montpellier, Unite Propre Rech 1142, CNRS, Inst Med Genet, F-34059 Montpellier, France

[14] Selcuk Univ, Meram Med Fac, Div Pediat Allergy & Immunol, Konya, Turkey

[15] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA

[16] Childrens Hosp, Dept Transfus Med, Boston, MA 02115 USA

[17] Univ Calif Los Angeles, Div Allergy & Immunol, Los Angeles, CA USA

[18] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA

来源：

NATURE IMMUNOLOGY | 2012年 / 13卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

SYK TYROSINE KINASE; TOLL-LIKE RECEPTORS; NF-KAPPA-B; IMMUNE-RESPONSES; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; STAT3; ACTIVATION; CPG ODN; INDUCTION; MYD88;

D O I：

10.1038/ni.2305

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-kappa B, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

引用

页码：612 / +

页数：11

共 54 条

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