Coinhibitory suppression of t cell activation by CD40 protects against obesity and adipose tissue inflammation in mice

Dennis Wolf, Felix Jehle, Nathaly Anto Michel, Eva Nora Bukosza, Jennifer Rivera, Yung Chih Chen, Natalie Hoppe, Bianca Dufner, Alexandra Ortiz Rodriguez, Christian Colberg, Leandro Nieto, Benjamin Rupprecht, Ansgar Wiedemann, Lisa Schulte, Alexander Peikert, Nicole Bassler, Andrey Lozhkin, Sonja Patricia Hergeth, Peter Stachon, Ingo HilgendorfFlorian Willecke, Constantin Von Zur Mühlen, Dominik von Elverfeldt, Christoph J. Binder, Peter Aichele, Nerea Varo, Mark A. Febbraio, Peter Libby, Christoph Bode, Karlheinz Peter, Andreas Zirlik

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45 Citations (Scopus)

Abstract

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. (Circulation. 2014;129:2414-2425.)

Original languageEnglish
Pages (from-to)2414-2425
Number of pages12
JournalCirculation
Volume129
Issue number23
DOIs
Publication statusPublished - 10 Jun 2014
Externally publishedYes

Keywords

  • Adipose tissue
  • CD40 ligand
  • Costimulatory and inhibitory T-cell receptors
  • Inflammation
  • Obesity

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