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

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.

HIV and antiretroviral therapy-related fat alterations

“…Interestingly, among PLWH seen in a European metabolic diseases clinic with a range of fat alteration phenotypes, circulating CD8 + T cell activation was higher in both patients with lipoatrophy and in those with central fat accumulation than in patients without clinically apparent fat redistribution 124 . In addition, CD8 + T cells in SAT from PLWH without clinically apparent lipodystrophy have increased antigen receptor clonality 120 , a finding which is also reported in animal models of obesity 125 . This finding could reflect local T cell expansion, although some studies have reported a lack of Ki-67 (a marker of proliferating cells) expression and high CD57 (a marker of late differentiation or senescence and an indicator of reduced replicative capacity) expression on CD8 + cells from adipose tissue of SIV-infected macaques, which could reflect minimal in situ proliferation 87,126,127 .…”

Enrichment of Tc1 cells and T cell resistance to suppression are associated with dysglycemia in the visceral fat in human obesity

“…14 Unexpectedly, the VAT of obese mice was found enriched with CD8 T cells with a clonal T cell receptor (TCR) repertoire, suggesting local expansion toward cognate antigens with a potential implication of antigen specificity in obesity. 15 T cells infiltrating the VAT have also been described in humans. Th1 and Tc1 cells were found increased, 16 while impaired T cell regulation was observed in the VAT of obese patients 14 when compared with subcutaneous adipose tissue (SAT) or with PB of the same patients.…”

Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond

“…CD8 + T cells appear to interact with adipocytes and macrophages in obese AT to trigger an inflammatory cascade via an interactive circle (57). A recent study raised the possibility that isolevuglandin-containing antigens presented by M2-polarized macrophages to CD8 + T cells in the AT of DIO mice may preferentially expand cognate TCR clonotypes (58). Thus, obesity-associated antigens may select and modify the TCR repertoire in the AT and thereby alter immune responses at adipose depots.…”