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Diabetes. 2018 Nov;67(11):2361-2376. doi: 10.2337/db18-0040. Epub 2018 Sep 4.

High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.

Author information

1
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.
2
Center for Translational Immunology and Infectious Disease, Vanderbilt University Medical Center, Nashville, TN.
3
Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN.
4
Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN.
5
Veterans Administration Tennessee Valley Healthcare System, Nashville, TN.
6
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
7
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
9
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN arion.kennedy@vanderbilt.edu.

Abstract

Adipose tissue (AT) CD4+ and CD8+ T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8+ and CD4+ TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8+ T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8+ T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8+ T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.

PMID:
30181158
PMCID:
PMC6198339
[Available on 2019-11-01]
DOI:
10.2337/db18-0040
[Indexed for MEDLINE]

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