Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes

Edner, Natalie M.; Heuts, Frank; Thomas, Niclas; Wang, Chun Jing; Petersone, Lina; Kenefeck, Rupert; Kogimtzis, Alexandros; Ovcinnikovs, Vitalijs; Ross, Ellen M.; Ntavli, Elisavet; Elfaki, Yassin; Eichmann, Martin; Baptista, Roman; Ambery, Philip; Jermutus, Lutz; Peakman, Mark; Rosenthal, Miranda; Walker, Lucy S. K.

doi:10.1038/s41590-020-0744-z

Cited by 75 publications

(60 citation statements)

References 51 publications

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“…By contrast, CD28 expression was only marginally detected across all perturbations, suggesting that CD28 signaling alone is sufficient for its internalization from the surface. Consistent with its known role as an inducible co-stimulatory molecule 45, 46 , we also found that CD278 ( ICOS ) expression could be promoted and sustained with intact CD28 signaling, independent of effective CD3E stimulation ( Fig. 6c ).…”

Section: Resultssupporting

confidence: 83%

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

Mimitou

Lareau

Chen

et al. 2020

Preprint

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Recent technological advances have enabled massively parallel chromatin profiling with single-cell Assay for Transposase Accessible Chromatin by sequencing (scATAC-seq) in thousands of individual cells. Here, we extend these approaches and present ATAC with Select Antigen Profiling by sequencing, ASAP-seq, a tool to simultaneously profile accessible chromatin and protein levels in thousands of single cells. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA (mtDNA) for clonal tracking, thus concomitantly capturing three distinct modalities in single cells. Importantly, ASAP-seq uses a novel bridging approach that repurposes antibody:oligo conjugates designed for existing technologies that pair protein measurements with single cell RNA-seq. We demonstrate the utility of ASAP-seq by revealing coordinated and distinct changes in chromatin, RNA, and surface proteins during native hematopoietic differentiation, peripheral blood mononuclear cell stimulation, and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells.

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Section: Resultssupporting

confidence: 83%

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

Mimitou

Lareau

Chen

et al. 2020

Preprint

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“…Though critical for generating appropriate B‐cell responses to infection and vaccination, dysregulated Tfh cell responses can occur and are associated with a variety of autoimmune and inflammatory disorders, many of which develop with increasing age. This suggests that age can impact Tfh cell development and/or function (Blanco et al, 2016; Deng et al, 2019; Edner et al, 2020; Qin et al, 2018; Vinuesa et al, 2016). In mice, age‐dependent changes in CD4 + T cells have been shown to contribute to the defective GC and antibody responses (Eaton et al, 2004; Lefebvre et al, 2016; Maue & Haynes, 2009; Yang et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

et al. 2021

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Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre‐Tfh) but no associated increase in germinal centre (GC)‐Tfh cells in aged mice, suggesting age‐driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age‐associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age‐induced changes in T‐cell activation that affects the differentiation and ultimately the function of effector T cells.

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“…Similar to MS, an increase in circulating T FH cells has been associated with type 1 diabetes (165)(166)(167). A recent study showed that abatacept was able to decrease T FH cells in a mouse model of type 1 diabetes, even after the disease is established (134). Furthermore, abatacept reduces circulating T FH cells in RA and in Sjögren's syndrome (168,169).…”

Section: Targeting T Fh Cells Via Cd28 and Icosmentioning

confidence: 98%

“…T FH cells are broadly identified as CXCR5 + PD-1 + BCL6 + ICOS + and their effector function is primarily associated with the secretion of IL-21 (91). This subset is most strongly linked to GC B cell responses and has only recently been included as a diseaserelevant subset in MS and other disease conditions (133,134). T FH cells have been associated with RA, SLE, and Sjögren's syndrome in a manner dependent on their ability to support GC B cell responses (135).…”

Section: T Fh Cells: Hurting More Than Helping?mentioning

confidence: 99%

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

2020

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While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.

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Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes

Cited by 75 publications

References 51 publications

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

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