Co-Inhibitory Suppression of T Cell Activation by CD40 Protects from Obesity and Adipose Tissue Inflammation in Mice
Background—Co-stimulatory 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 (DIO) in mice.
Methods and Results—To induce the metabolic syndrome, WT 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 pro-inflammatory gene expression. This pro-inflammatory and adverse metabolic phenotype could be transplanted into WT mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 on 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 expression of pro-inflammatory cytokines in T cells, but not in B cells or macrophages. Finally, re-population 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 sCD40 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, while activation of CD40 signaling improves, adipose tissue inflammation and its metabolic complications. Positive modulation of the CD40 pathway might, therefore, describe a novel therapeutic concept against cardio-metabolic disease.
- Received December 7, 2013.
- Revision received March 9, 2014.
- Accepted March 18, 2014.