Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

被引：97

作者：

Bobr, Aleh ^{[1
]}

Igyarto, Botond Z. ^{[1
]}

Haley, Krystal M. ^{[1
]}

Li, Ming O. ^{[2
]}

Flavell, Richard A. ^{[3
,4
]}

Kaplan, Daniel H. ^{[1
]}

机构：

[1] Univ Minnesota, Dept Dermatol, Ctr Immunol, Minneapolis, MN 55455 USA

[2] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA

[3] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA

[4] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 26期

基金：

美国国家卫生研究院;

关键词：

skin immunology; pSMAD2/3; tolerance; TGF-BETA; DENDRITIC CELLS; IN-VIVO; CONTACT HYPERSENSITIVITY; STEADY-STATE; SKIN; MICE; DIFFERENTIATION; ACTIVATION; MONOCYTES;

D O I：

10.1073/pnas.1119178109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-beta 1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-beta 1 is complicated by the requirement of TGF-beta 1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-beta 1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER(T2) mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER(T2) x TGF-beta RIIfl and huLangerin-CreER(T2) x TGF-beta 1(fl) mice. Excision of the TGF beta RII or TGF beta 1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-beta 1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammation-induced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.

引用

页码：10492 / 10497

页数：6

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