title: CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity.
abstract: Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan, USA;
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Literature, Science and Arts Program, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Kelsie E
authors.initials: KE
authors.lastname: Oatmen
authors.affiliation: Literature, Science and Arts Program, University of Michigan, Ann Arbor, Michigan, USA;
authors.forename: Taleen A
authors.initials: TA
authors.lastname: Mergian
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan, USA;
authors.forename: Kae Won
authors.initials: KW
authors.lastname: Cho
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan, USA;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: DelProposto
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan, USA;
authors.forename: Kanakadurga
authors.initials: K
authors.lastname: Singer
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Surgery, Ann Arbor Veteran's Administration Hospital, Ann Arbor, Michigan, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: O'Rourke
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan, USA; clumeng@umich.edu.
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D059305:Diet, High-Fat; D006410:Hematopoiesis / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000276:immunology* / Q000473:pathology; D009852:Omentum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D023201:CD40 Ligand
keywords: CD40L; antigen presenting cells (APC); inflammation