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 3

Adipose PD-1+CD4+ T cells secrete a large amount of OPN at the cost of normal function.

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Adipose PD-1+CD4+ T cells secrete a large amount of OPN at the cost of n...
PD-1+ and PD-1–CD4+ T cells were separately isolated from VAT of 18-week-old HFD-fed mice. (A) VAT PD-1+ and PD-1–CD4+ T cells were cultured in the presence or absence of anti-CD3 and anti-CD28 mAb for 3 days. IL-2 and IFN-γ in the culture supernatants (sup.) were assessed on day 3 by ELISA (n = 3 mice per group). (B) VAT PD-1+ and PD-1–CD4+ T cells were analyzed for Satb1 and Cebpa mRNA expression by real-time PCR (n = 5 mice per group). (C) VAT PD-1+ and PD-1–CD4+ T cells were cultured in the presence or absence of anti-CD3 and anti-CD28 mAb for 3 days. OPN in the culture supernatants was assessed on day 3 by ELISA (n = 3 mice per group). (D) Serum OPN levels in mice fed an ND or HFD for 14 weeks (n = 5 mice per group). (E) Representative flow cytometric analysis demonstrating SA–β-gal activity. (F) Representative flow cytometric analysis demonstrating the phosphorylated histone H2AX at serine 139 (referred to as γ-H2AX) of VAT CD4+ T cells. Flow cytometric plots are representative of at least 3 independent experiments. Data represent the mean ± SEM. *P < 0.05 and ***P < 0.0001, by 2-tailed Student’s t test.