Pathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis

Lee, Hong-Gyun; Lee, Jae-Ung; Kim, Do Hyun; Lim, Su-Ho; Kang, Insoo; Choi, Je-Min

doi:10.1038/s41467-019-08482-w

Cited by 57 publications

(72 citation statements)

References 58 publications

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“…IL-1β enhanced post-transcriptional stability of effector cytokines such as TH17 cytokines, IL-5 and IL-13 via the p38 MAPK pathway in the murine CD4 EM T cells 17 . Other studies, mostly murine, also demonstrated that IL-1β is crucial for proinflammatory cytokine production by CD4 EM T cells through activation of NF-kB, p38 and JNK 15,16,[18][19][20][21] . Consistent with these studies, our CyTOF analyses in human immune cells demonstrated IL-1β-induced signaling predominantly in the CD4 EM subsets including TH17, Tfh and MTregs.…”

Section: Discussionmentioning

confidence: 99%

“…A 35 antibody panel was developed based on a comprehensive review of the literature on IL-1βinduced effects on immune cells [15][16][17][18][19][20][21][22][23] (Fig. 1a and Supplementary Table 1) and optimized ( Supplementary Figs.…”

Section: Il-1β Induced Early Increases In P-nf-kb and P-p38 In Distinmentioning

confidence: 99%

“…NF-κB, p38 MAPK, ERK and JNK activation have been implicated in IL-1R1-mediated immune cell activation [15][16][17][18][19][20][21][22][23] . Notably, the majority of these are murine studies.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

Kothari

Williams

McSkimming

et al. 2020

Preprint

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IL-1β has emerged as a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19 and blockade of the IL-1 receptor (IL-1R) with Anakinra has entered clinical trials in COVID-19 subjects. Yet, knowledge of the specific immune cell subsets targeted by IL-1β and IL-1β-induced signaling pathways in humans is limited. Utilizing mass cytometry (CyTOF) of human peripheral blood mononuclear cells, we identified effector memory CD4 T cells and CD4 -CD8 low/-CD161 + T cells as the circulating immune subtypes with the greatest expression of p-NF-κB in response to IL-1β stimulation.Notably, CCR6 distinctly identified T cells most responsive to IL-1β. Other subsets including CD11c myeloid dendritic cells (mDCs), classical monocytes (CM), two subsets of natural killer cells (CD16 -CD56 bright CD161and CD16 -CD56 dim CD161 + ) and a population of lineage -(Lin-) cells expressing CD161 and CD25 also showed IL-1β-induced expression of p-NF-kB. The IL-1R antagonist, Anakinra significantly inhibited IL-1β-induced p-NF-kB in the CCR6 + T cells and CD11c mDCs with a trending inhibition in CD14 monocytes and Lin -CD161 + CD25 + cells. IL-1β also induced a rapid but much less robust increase in p-p38 expression as compared to p-NF-kB in the majority of these same immune cell subsets. Prolonged IL-1β stimulation greatly increased p-STAT3 and to a much lesser extent p-STAT1 and p-STAT5 in T cell subsets, monocytes, DCs and the Lin -CD161 + CD25 + cells suggesting IL-1βinduced production of downstream STAT-activating cytokines, consistent with its role in cytokine storm.Interindividual heterogeneity and inhibition of this activation by Anakinra raises the intriguing possibility that assays to measure IL-1β-induced p-NF-kB in CCR6 + T cell subtypes could identify those at higher risk of cytokine storm and those most likely to benefit from Anakinra therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Il-1β Induced Early Increases In P-nf-kb and P-p38 In Distinmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

Kothari

Williams

McSkimming

et al. 2020

Preprint

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“…T cell receptor (TCR) specificity can play a vital role in those lineages’ polarization [ 3 , 4 , 5 ]. However, experiments carried out on mouse models with transgenic T cell receptors and nextgen sequence (NGS) data from T cell repertoires has revealed that, in some circumstances, clones that express a particular TCR exhibit divergent capability in terms of functional specialization in peripheral organs [ 6 , 7 ]. This promiscuity of the TCR in the context of different T cell lineages indicates a huge plasticity within the adaptive compartment and a complex network of interacting components involved in building up niches for specific cell subsets.…”

Section: Introductionmentioning

confidence: 99%

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

Wojciech

Tan

Gascoigne

2020

IJMS

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A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut microbiome’s complexity with host physiology. Hence, understanding the mechanistic aspects underlying the synergy between the host and its associated gut microbiome are among the most crucial questions. The functionally diversified adaptive immune system plays a central role in maintaining gut and systemic immune homeostasis. The character of the reciprocal interactions between immune components and host-dwelling microbes or microbial consortia determines the outcome of the organisms’ coexistence within the holobiont structure. It has become apparent that metabolic by-products of the microbiome constitute crucial multimodal transmitters within the host–microbiome interactome and, as such, contribute to immune homeostasis by fine-tuning of the adaptive arm of immune system. In this review, we will present recent insights and discoveries regarding the broad landscape of microbiome-derived metabolites, highlighting the role of these small compounds in the context of the balance between pro- and anti-inflammatory mechanisms orchestrated by the host T cell compartment.

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“…Two major hypotheses have been postulated to explain mechanism of the expansion of Tcells in the context of autoimmunity [26] , [27]. The first hypothesis states that T-cells might expand non-specifically or by chance (bystander activation) due to chronic inflammation observed in autoimmune patients [27,28] , [29]. In this case, proliferation of T-cells is induced through non-specific activation in the presence of TLR ligands and cytokines during an immune response.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal analysis of T-cell receptor repertoires reveals persistence of antigen-driven CD4+ and CD8+ T-cell clusters in Systemic Sclerosis

Servaas

Zaaraoui-Boutahar

Kommer-Wichers

et al. 2020

Preprint

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The T-cell receptor (TCR) is a highly polymorphic surface receptor that allows T-cells to recognize antigenic peptides presented on the major histocompatibility complex (MHC). Changes in the TCR repertoire have been observed in several autoimmune conditions, and these changes are suggested to predispose autoimmunity. Multiple lines of evidence have implied an important role for T-cells in the pathogenesis of Systemic Sclerosis (SSc), a complex autoimmune disease. One of the major questions regarding the roles of T-cells is whether expansion and activation of T-cells observed in the diseases pathogenesis is (auto)antigen driven. To investigate the temporal TCR repertoire dynamics in SSc, we performed high-throughput sequencing of CD4+ and CD8+ TCRβ chains on longitudinal samples obtained from four SSc patients collected over a minimum of two years. Repertoire overlap analysis revealed that samples taken from the same individual over time shared a high number of TCRβ sequences, indicating a clear temporal persistence of the TCRβ repertoire in CD4+ as well as CD8+ T-cells. Moreover, the TCRβs that were found with a high frequency at one time point were also found with a high frequency at the other time points (even after almost four years), showing that frequencies of dominant TCRβs are largely consistent over time. We also show that TCRβ generation probability and observed TCR frequency are not related in SSc samples, showing that clonal expansion and persistence of TCRβs is caused by antigenic selection rather than convergent recombination. Moreover, we demonstrate that TCRβ diversity is lower in CD4+ and CD8+ T-cells from SSc patients compared to healthy memory T-cells, as SSc TCRβ repertoires are largely dominated by clonally expanded persistent TCRβ sequences. Lastly, using 'Grouping of Lymphocyte Interactions by Paratope Hotspots' (GLIPH2), we identify clusters of TCRβ sequences with homologous sequences that potentially recognize the same antigens and contain TCRβs that are persist in SSc patients. In conclusion, our results show that that CD4+ and CD8+ T-cells are highly persistent in SSc patients over time, and this persistence is likely a result from antigenic selection. Moreover, persistent TCRs form high similarity clusters with other (non-)persistent sequences, that potentially recognize the same epitopes. These data provide evidence for an (auto-)antigen driven expansion of CD4/CD8+ T-cells in SSc.

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Pathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis

Cited by 57 publications

References 58 publications

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

Longitudinal analysis of T-cell receptor repertoires reveals persistence of antigen-driven CD4+ and CD8+ T-cell clusters in Systemic Sclerosis

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