Article | Published:

CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity

Nature Medicine volume 15, pages 914920 (2009) | Download Citation

Subjects

Abstract

Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8+ effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4+ helper and regulatory T cells were diminished. The infiltration by CD8+ T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8+ T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8+ T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8+ T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8+ T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

  2. 2.

    et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

  3. 3.

    et al. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J. Clin. Invest. 118, 710–721 (2008).

  4. 4.

    et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

  5. 5.

    , & Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 (2007).

  6. 6.

    , , & Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).

  7. 7.

    , & Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

  8. 8.

    , & A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 25, 2062–2068 (2005).

  9. 9.

    et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038 (2007).

  10. 10.

    , , & Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int. J. Obes. (Lond.) 32, 451–463 (2008).

  11. 11.

    et al. TH1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

  12. 12.

    , , , & ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice. Am. J. Physiol. Cell Physiol. 291, C1232–C1239 (2006).

  13. 13.

    et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location and stabilize endothelial networks. Circ. Res. 102, 77–85 (2008).

  14. 14.

    et al. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells and blood vessels. Diabetes 56, 1517–1526 (2007).

  15. 15.

    et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

  16. 16.

    , , , & Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

  17. 17.

    , & Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

  18. 18.

    et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28, 1304–1310 (2008).

  19. 19.

    , , , & Cytokine production of CD8+ immune T cells but not of CD4+ T cells from Toxoplasma gondii–infected mice is polarized to a type 1 response following stimulation with tachyzoite-infected macrophages. J. Interferon Cytokine Res. 26, 787–792 (2006).

  20. 20.

    et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006).

  21. 21.

    et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum. Immunol. 66, 222–230 (2005).

  22. 22.

    et al. CD4+CD25+ regulatory T cells protect against injury in an innate murine model of chronic kidney disease. J. Am. Soc. Nephrol. 17, 2731–2741 (2006).

Download references

Acknowledgements

We gratefully acknowledge A. Matsuoka, X. Yingda, E. Magoshi, M. Hayashi, K. Wakabayashi, M. Tajima and Y. Yamazaki for excellent technical assistance. This study was supported by Research Fellowships from the Japan Society for the Promotion of Science for Young Scientists (S.N.), Grants-in-Aid for Scientific Research (I.M., R.N.) and grants for Translational Systems Biology and Medicine Initiative (R.N., T.K.) and Global Centers of Excellence program (R.N., T.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a research grant from the National Institute of Biomedical Innovation (R.N.).

Author information

Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Satoshi Nishimura
    • , Ichiro Manabe
    • , Mika Nagasaki
    • , Hiroshi Yamashita
    •  & Ryozo Nagai
  2. Nano-Bioengineering Education Program, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Satoshi Nishimura
    •  & Ichiro Manabe
  3. Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Satoshi Nishimura
    • , Kohjiro Ueki
    • , Takashi Kadowaki
    •  & Ryozo Nagai
  4. PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan.

    • Satoshi Nishimura
    •  & Ichiro Manabe
  5. Comprehensive Center of Education and Research for Chemical Biology of the Diseases, The University of Tokyo, Tokyo, Japan.

    • Ichiro Manabe
    • , Kohjiro Ueki
    • , Takashi Kadowaki
    •  & Ryozo Nagai
  6. Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo, Tokyo, Japan.

    • Mika Nagasaki
  7. Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Koji Eto
    •  & Makoto Otsu
  8. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Mitsuru Ohsugi
    • , Kazuo Hara
    • , Kohjiro Ueki
    •  & Takashi Kadowaki
  9. Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

    • Seiryo Sugiura
  10. Department of Plastic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Kotaro Yoshimura

Authors

  1. Search for Satoshi Nishimura in:

  2. Search for Ichiro Manabe in:

  3. Search for Mika Nagasaki in:

  4. Search for Koji Eto in:

  5. Search for Hiroshi Yamashita in:

  6. Search for Mitsuru Ohsugi in:

  7. Search for Makoto Otsu in:

  8. Search for Kazuo Hara in:

  9. Search for Kohjiro Ueki in:

  10. Search for Seiryo Sugiura in:

  11. Search for Kotaro Yoshimura in:

  12. Search for Takashi Kadowaki in:

  13. Search for Ryozo Nagai in:

Contributions

S.N. and M.N. performed in vivo and in vitro assays and analyzed all of the end points. K.H., K.U. and K.Y. performed human subject assays. S.N., I.M., K.E., H.Y., M. Otsu, M. Ohsugi, S.S., T.K. and R.N. supervised entire studies. S.N. and I.M. wrote the manuscript.

Corresponding authors

Correspondence to Satoshi Nishimura or Ichiro Manabe.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Table 1 and Supplementary Figs. 1–12

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.1964

Further reading