Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells

Truong, Kim-Long; Schlickeiser, Stephan; Vogt, Katrin; Boës, David; Stanko, Katarina; Appelt, Christine; Streitz, Mathias; Grütz, Gerald; Stobutzki, Nadja; Meisel, Christian; Iwert, Christina; Tomiuk, Stefan; Polansky, Julia K.; Pascher, Andreas; Babel, Nina; Stervbo, Ulrik; Sauer, Igor M.; Gerlach, Undine; Sawitzki, Birgit

doi:10.1038/s41467-019-10018-1

Cited by 63 publications

(59 citation statements)

References 61 publications

(69 reference statements)

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“…5c). Genes ( KLRF1, FGFBP2, and PTGDS) upregulated in PA T-cells cluster within an offshoot off the main body of the UMAP plot suggesting a progression towards terminally differentiated effector memory T-cells in the PA. FGFBP2 is associated with T-cell effector functions 19 , and KLFR1 is a marker for CD4+ T-cell exhaustion and decline of cytokine releasing potential 20 . Its overexpression in the PA region suggests antigen-persistence occurs anatomically in atherogenesis.…”

Section: Resultsmentioning

confidence: 99%

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Alsaigh¹,

Evans²,

Frankel

et al. 2020

Preprint

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Atherogenesis involves an interplay of inflammation, tissue remodeling and cellular transdifferentiation (CTD), making it especially difficult to precisely delineate its pathophysiology. Here we examine the single-cell transcriptome of entire atherosclerotic core (AC) plaques and patient-matched proximal adjacent (PA) portions of carotid artery tissue from patients undergoing carotid endarterectomy. We use a novel tissue dissociation strategy, single-cell RNA sequencing, and systems-biology approaches to analyze the transcriptional profiles of six main cell populations and identify key gene drivers of pathogenic biological processes in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Our results reveal an anatomic continuum whereby PA cells promote and respond to inflammatory processes and eventually transition through CTD into matrix-secreting cells in the AC. Inflammatory signaling in PA ECs is driven by IL6, while TNFa signaling defines inflammation in both PA ECs and VSMCs. Furthermore, we identify POSTN, SPP1 and IBSP in AC VSMCs, and ITLN1, SCX and S100A4 in AC ECs as key drivers of CTD in the atherosclerotic core. These results establish an anatomic framework for atherogenesis and suggest a site-specific strategy for disruption of disease progression.

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Section: Resultsmentioning

confidence: 99%

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Alsaigh¹,

Evans²,

Frankel

et al. 2020

Preprint

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“…Recent studies of CD4 + T EMRA cells have identified major subsets based on G protein-coupled receptor GPR56 expression, with virus-specific cells more frequently GPR56 + and more clonally expanded compared to GPR56 − cells ( 52 ). Increased expression of GPR56 and killer-like receptors (KLR) has been linked to higher cytokine expression by memory CD4 + T cells, including T cells obtained from liver tissue ( 53 ). CD4 + and CD8 + T EMRA cytotoxic T cells expressing GPR56 have also been associated with increased co-expression of CX 3 CR1 ( 52 , 54 , 55 ).…”

Section: Resultsmentioning

confidence: 99%

Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance

et al. 2019

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Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100–125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO−CCR7+, effector memory (TEM) CD45RO+CCR7−, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO−CCR7− CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.

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“…Virus-specific T EMRA cells are more frequently GPR56 + , 16 and increased expression of GPR56 and killer-like receptors (KLRs) has been linked to higher CD4 + T cell cytokine expression. 17 Furthermore, cytotoxic GPR56 + CD4 + and CD8 + T EMRA cells have higher co-expression of the CX3CR1 receptor, 16 , 18 , 19 which is also a marker of anti-cytomegalovirus (CMV) T cells. 19 , 20 , 21 , 22 Given that adipose tissue serves as a reservoir for latently HIV-infected CD4 + T cells, free HIV RNA virus, and CMV, 2 , 3 , 6 , 23 greater C-G-C + co-expression on CD4 + T cells in adipose tissue of HIV-positive diabetics may reflect a cytotoxic response by virus-specific cells that adversely affects bystander adipocytes and contributes to metabolic disease.…”

Section: Introductionmentioning

confidence: 99%