Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

Glinos, Dafni A.; Soskic, Blagoje; Jostins, Luke; Sansom, David M.; Trynka, Gosia

doi:10.1101/421099

Cited by 5 publications

(5 citation statements)

References 73 publications

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“…Our new data suggest a continuous requirement for CD28 signalling to sustain ICOS expression, implying that this hierarchy is perpetuated even after T cell activation. Consistent with this, RNAseq analysis identified Icos to be highly CD28-sensitive in human memory T cells 46 .…”

Section: Discussionsupporting

confidence: 56%

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

et al. 2020

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Follicular helper T cells (Tfh) are implicated in type 1 diabetes (T1D) and their development has been linked to CD28 costimulation. We tested whether Tfh were decreased by costimulation blockade using the CTLA-4-Ig fusion protein (Abatacept) in a mouse model of diabetes and in individuals with new onset T1D. Unbiased bioinformatic analysis identified that ICOS + Tfh, and other ICOS + populations including T-peripheral helper cells, were highly sensitive to costimulation blockade. We were able to use pre-treatment Tfh profiles to derive a model that could predict clinical response to Abatacept in individuals with T1D. Using two independent approaches we demonstrated that higher frequencies of ICOS + Tfh at baseline were associated with a poor clinical response following Abatacept administration. Tfh analysis may therefore represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.

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Section: Discussionsupporting

confidence: 56%

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

et al. 2020

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“…These stimuli were applied to memory and naive CD4+ T cells, which constitute the two major subsets of CD4+ T cells. We treated naive and memory cells separately because the two subsets differ in their response to stimulation 16 . Given that the response to stimulation develops over time 17 , we profiled T cells during both early and late activation.…”

Section: Overview Of the Experimental Designmentioning

confidence: 99%

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

et al. 2019

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Immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. We stimulated T cells and macrophages in the presence of thirteen cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while cytokines fine-tuned the Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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“…Sequencing libraries were generated from tagmented DNA using the Nextera® DNA library preparation kit according to the manufacturer's instructions. Briefly, DNA was amplified by PCR and fragments of inappropriate sizes were removed using Agencourt AMPure XP beads 16 (BD). Finally, samples were pooled and loaded into an Illumina® HiSeq 2500 for paired-end sequencing.…”

Section: Atac-seqmentioning

confidence: 99%

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Soskic

Cano-Gamez

Smyth

et al. 2019

Preprint

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Complex immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states or stages of cell activation is unknown. We stimulated T cells and macrophages in the presence of thirteen different cytokine cocktails linked to immune diseases and profiled active enhancers and promoters together with regions of open chromatin. We observed that T cell activation induced major chromatin remodelling, while additional exposure to cytokines fine-tuned the magnitude of these changes. Therefore, we developed a new statistical method that accounts for subtle changes in chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune disease variants in early rather than late activation of memory CD4+ T cells, and with limited differences across polarizing cytokines. Furthermore, we demonstrate that inflammatory bowel disease variants are enriched in chromatin regions active in Th1 cells, while asthma variants overlap regions active in Th2 cells. We also show that Alzheimer's disease variants are enriched in different macrophage cell states. Our results represent the first in-depth analysis of immune disease variants across a comprehensive panel of activation states of T cells and macrophages.

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Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

Abstract: 20One-sentence summary: 40 Genomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.

Cited by 5 publications

References 73 publications

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

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

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

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