High CD8 T-cell receptor clonality and altered CDR3 properties are associated with elevated isolevuglandins in adipose tissue during diet-induced obesity

W.J. McDonnell; J.R. Koethe; S.A. Mallal; M.A. Pilkinton; A. Kirabo; M.K. Ameka; M.A. Cottam; A.H. Hasty; A.J. Kennedy

doi:10.2337/db18-0040

Back

High CD8 T-cell receptor clonality and altered CDR3 properties are associated with elevated isolevuglandins in adipose tissue during diet-induced obesity

Journal article

Peer reviewed

High CD8 T-cell receptor clonality and altered CDR3 properties are associated with elevated isolevuglandins in adipose tissue during diet-induced obesity

W.J. McDonnell, J.R. Koethe, S.A. Mallal, M.A. Pilkinton, A. Kirabo, M.K. Ameka, M.A. Cottam, A.H. Hasty and A.J. Kennedy

Diabetes, Vol.67(11), pp.2361-2376

2018

DOI: https://doi.org/10.2337/db18-0040

Files and links (1)

url

Link to Published Version *Subscription may be requiredView

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.

Details

Title: High CD8 T-cell receptor clonality and altered CDR3 properties are associated with elevated isolevuglandins in adipose tissue during diet-induced obesity
Authors/Creators: W.J. McDonnell (Author/Creator) - Vanderbilt University
J.R. Koethe (Author/Creator) - Vanderbilt University Medical Center
S.A. Mallal (Author/Creator) - Vanderbilt University
M.A. Pilkinton (Author/Creator) - Vanderbilt University Medical Center
A. Kirabo (Author/Creator) - Vanderbilt University Medical Center
M.K. Ameka (Author/Creator) - Vanderbilt University
M.A. Cottam (Author/Creator) - Vanderbilt University
A.H. Hasty (Author/Creator) - Vanderbilt University
A.J. Kennedy (Author/Creator) - Vanderbilt University
Publication Details: Diabetes, Vol.67(11), pp.2361-2376
Publisher: American Diabetes Association
Identifiers: 991005543964607891
Copyright: © 2018 by the American Diabetes Association
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Metrics

31 Record Views

45 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.26 Diabetes; 1.26.107 Metabolic Syndrome
Web Of Science research areas: Endocrinology & Metabolism
ESI research areas: Clinical Medicine