Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

被引：54

作者：

Wolf, Dennis ^{[1
]}

Jehle, Felix ^{[1
,3
]}

Michel, Nathaly Anto ^{[1
]}

Bukosza, Eva Nora ^{[1
]}

Rivera, Jennifer ^{[3
]}

Chen, Yung Chih ^{[3
]}

Hoppe, Natalie ^{[1
]}

Dufner, Bianca ^{[1
]}

Rodriguez, Alexandra Ortiz ^{[1
]}

Colberg, Christian ^{[1
,3
]}

Nieto, Leandro ^{[1
]}

Rupprecht, Benjamin ^{[1
]}

Wiedemann, Ansgar ^{[1
]}

Schulte, Lisa ^{[1
]}

Peikert, Alexander ^{[1
]}

Bassler, Nicole ^{[3
]}

Lozhkin, Andrey ^{[1
]}

Hergeth, Sonja Patricia ^{[1
]}

Stachon, Peter ^{[1
]}

Hilgendorf, Ingo ^{[1
]}

Willecke, Florian ^{[1
]}

von zur Muehlen, Constantin ^{[1
]}

von Elverfeldt, Dominik ^{[4
]}

Binder, Christoph J. ^{[5
,6
]}

Aichele, Peter ^{[2
]}

Varo, Nerea ^{[7
]}

Febbraio, Mark A. ^{[3
]}

Libby, Peter ^{[8
]}

Bode, Christoph ^{[1
]}

Peter, Karlheinz ^{[3
]}

Zirlik, Andreas ^{[1
]}

机构：

[1] Univ Freiburg, Univ Heart Ctr, Atherogenesis Res Grp, D-79106 Freiburg, Germany

[2] Univ Freiburg, Dept Immunol, Inst Med Microbiol & Hyg, D-79106 Freiburg, Germany

[3] Baker IDI Heart & Diabet Inst, Melbourne, Vic 8008, Australia

[4] Univ Hosp Freiburg, Dept Diagnost Radiol Med Phys, Freiburg, Germany

[5] Med Univ Vienna, Dept Lab Med, Vienna, Austria

[6] Austrian Acad Sci, Ctr Mol Med, A-1010 Vienna, Austria

[7] Univ Navarra, Ctr Appl Med Res, Div Cardiovasc Sci, E-31080 Pamplona, Spain

[8] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA

来源：

CIRCULATION | 2014年 / 129卷 / 23期

基金：

英国医学研究理事会;

关键词：

adipose tissue; CD40; ligand; costimulatory and inhibitory T-cell receptors; inflammation; obesity; INSULIN-RESISTANCE; METABOLIC-DISORDERS; HEPATIC STEATOSIS; IMMUNE-SYSTEM; DISEASE; ANTIBODIES; TNF; ATHEROSCLEROSIS; ACCUMULATION; RECRUITMENT;

D O I：

10.1161/CIRCULATIONAHA.113.008055

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. Methods and Results-To induce the metabolic syndrome, wild-type or CD40(-/-) mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40(-/-) mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1(-/-) mice with CD40(-/-) T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. Conclusions-We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.

引用

页码：2414 / +

页数：37

共 42 条

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