Obesity accelerates T cell senescence in murine visceral adipose tissue
Kohsuke Shirakawa, … , Nagahiro Minato, Motoaki Sano
Kohsuke Shirakawa, … , Nagahiro Minato, Motoaki Sano
Published November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4626-4639. https://doi.org/10.1172/JCI88606.
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Research Article Immunology Metabolism

Obesity accelerates T cell senescence in murine visceral adipose tissue

Abstract

Chronic inflammation in visceral adipose tissue (VAT) precipitates the development of cardiometabolic disorders. Although changes in T cell function associated with visceral obesity are thought to affect chronic VAT inflammation, the specific features of these changes remain elusive. Here, we have determined that a high-fat diet (HFD) caused a preferential increase and accumulation of CD44hiCD62LloCD4+ T cells that constitutively express PD-1 and CD153 in a B cell–dependent manner in VAT. These cells possessed characteristics of cellular senescence and showed a strong activation of Spp1 (encoding osteopontin [OPN]) in VAT. Upon T cell receptor stimulation, these T cells also produced large amounts of OPN in a PD-1–resistant manner in vitro. The features of CD153+PD-1+CD44hiCD4+ T cells were highly reminiscent of senescence-associated CD4+ T cells that normally increase with age. Adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells from HFD-fed WT, but not Spp1-deficient, mice into the VAT of lean mice fed a normal diet recapitulated the essential features of VAT inflammation and insulin resistance. Our results demonstrate that a distinct CD153+PD-1+CD44hiCD4+ T cell population that accumulates in the VAT of HFD-fed obese mice causes VAT inflammation by producing large amounts of OPN. This finding suggests a link between visceral adiposity and immune aging.

Authors

Kohsuke Shirakawa, Xiaoxiang Yan, Ken Shinmura, Jin Endo, Masaharu Kataoka, Yoshinori Katsumata, Tsunehisa Yamamoto, Atsushi Anzai, Sarasa Isobe, Naohiro Yoshida, Hiroshi Itoh, Ichiro Manabe, Miho Sekai, Yoko Hamazaki, Keiichi Fukuda, Nagahiro Minato, Motoaki Sano

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Figure 6

Adipose CD153+PD-1+CD4+ T cells are the main source of OPN in VAT of HFD-fed mice.

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Adipose CD153+PD-1+CD4+ T cells are the main source of OPN in VAT of HFD...
(A) Representative flow cytometric analysis demonstrating the expression of FoxP3, GATA3, T-bet, and RORγt in CD153+PD-1+CD4+ T cells. (B) PD-1–, CD153–PD-1+, and CD153+PD-1+CD4+ T cells were separately isolated from VAT of WT mice fed an HFD. The indicated CD4+ T cells were cultured in the presence of anti-CD3/CD28 mAb for 3 days. IFN-γ and OPN concentrations in the culture supernatants were assessed by ELISA (n = 5 mice per group). *P < 0.05 and ***P < 0.0001, by ANOVA followed by post hoc Bonferroni tests. (C) Representative flow cytometric analysis of EGFP-Spp1 in PD-1+CD4+ T cells obtained from VAT of EGFP-Spp1–KI reporter mice fed an HFD (far left). CD153+ and EGFP-Spp1 in PD-1hi, PD-1lo, and PD-1nullCD4+ T cells obtained from VAT of EGFP-Spp1–KI reporter mice fed an HFD (right 3 panels). (D) Representative flow cytometric analysis of EGFP-Spp1 in the indicated cells obtained from VAT of EGFP-Spp1–KI reporter mice fed an HFD. Red box shows high fluorescence intensity of GFP in CD153+PD-1+CD4+ T cells. (E) Representative flow cytometric analysis of EGFP-Spp1 in CD8+ T cells, B cells, and macrophages obtained from the VAT of EGFP-Spp1–KI reporter mice fed an HFD. Flow cytometric plots are representative of at least 3 independent experiments. Data represent the mean ± SEM.