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Transcriptional profiling of individual naïve CD4 T cells sorted across the full spectrum of self-reactivity [scRNA-seq]

ABSTRACT: Transcriptional profiling of individual naïve CD4 T cells sorted across the full spectrum of self-reactivity [scRNA-seq]

PROVIDER: PRJNA770369 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16292732_1.fastq.gz	Fastqsanger.gz
	SRR16292732_2.fastq.gz	Fastqsanger.gz
	SRR16292733_1.fastq.gz	Fastqsanger.gz
	SRR16292733_2.fastq.gz	Fastqsanger.gz
	SRR16292734_1.fastq.gz	Fastqsanger.gz

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Transcriptional profiling of individual naïve CD4 T cells sorted across the full spectrum of self-reactivity [scRNA-seq]

Project description:Transcriptional characterization of naïve CD4 T cells across the spectrum of self-reactivity at the single cell level

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Machine learning analysis of the T cell receptor repertoire identifies sequence features that predict self-reactivity

Project description:The T cell receptor (TCR) determines the specificity and affinity for both foreign and self-peptides presented by MHC. It is established that self-pMHC reactivity impacts T cell function, but it has been challenging to identify TCR sequence features that predict T cell fate. To discern patterns distinguishing TCRs from naïve CD4+ T cells with low versus high self-pMHC reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that predicts self-reactivity directly from TCRβ sequences. This approach revealed that n-nucleotide additions and acidic amino acids weaken selfreactivity. We tested our ML predictions of TCRβ sequence self-reactivity using retrogenic mice. Extrapolating our analyses to independent datasets, we found high predicted self-reactivity for regulatory CD4+ T cells and low predicted self-reactivity for T cells responding to chronic infection. Our analyses suggest a potential trade-off between repertoire diversity and self-reactivity intrinsic to the architecture of a TCR repertoire.

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T cell self-reactivity during thymic development dictates the timing of positive selection

Project description:Functional tuning of mature T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity down-regulate TCR sensitivity more slowly during positive selection, and suggest that modulation of membrane ion channel function may play a role in regulating TCR tuning throughout development.

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Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

Project description:The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in inflammatory disease models. The differential ability of Tc17 differentiation was not related to T-cell receptor (TCR) diversity and antigen specificity but was inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon was linked to differential levels of intrinsic TCR sensitivity and basal SMAD3 expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

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CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells

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