Impact of secondary TCR engagement on the heterogeneity of pathogen-specific CD8+ T cell response during acute and chronic toxoplasmosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA779071 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16892819.fastq.gz | Fastqsanger.gz | |||
| SRR16892820.fastq.gz | Fastqsanger.gz | |||
| SRR16892821.fastq.gz | Fastqsanger.gz | |||
| SRR16892822.fastq.gz | Fastqsanger.gz | |||
| SRR16892823.fastq.gz | Fastqsanger.gz |
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Project description:Initial TCR-dependent engagement of CD8+ T cells results in T cell expansion, and the early events involved in priming influence the generation of diverse effector and memory populations. During infection, some of these activated T cells re-encounter cognate antigen, but whether this influences phenotypic heterogeneity is unclear. To address this issue, OT-I T cells, which are specific for the SIINFEKL peptide from OVA and express the Nur77-GFP reporter of recent TCR activation, were paired with transgenic T. gondii that express OVA to assess the impact of TCR activation on parasite-specific CD8+ T cell responses.
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Project description:Initial TCR engagement (priming) of naive CD8+ T cells results in T cell expansion, and these early events influence the generation of diverse effector and memory populations. During infection, activated T cells can re-encounter cognate antigen, but how these events influence local effector responses or formation of memory populations is unclear. To address this issue, OT-I T cells which express the Nur77-GFP reporter of TCR activation were paired with the parasite Toxoplasma gondii that expresses OVA to assess how secondary encounter with antigen influences CD8+ T cell responses. During acute infection, TCR stimulation in affected tissues correlated with parasite burden and was associated with markers of effector cells while Nur77-GFP- OT-I showed signs of effector memory potential. However, both Nur77-GFP- and Nur77-GFP+ OT-I from acutely infected mice formed similar memory populations when transferred into naive mice. During the chronic stage of infection in the CNS, TCR activation was associated with large scale transcriptional changes and the acquisition of an effector T cell phenotype as well as the generation of a population of CD103+ CD69+ Trm like cells. While inhibition of parasite replication resulted in reduced effector responses it did not alter the Trm population. These data sets highlight that recent TCR activation contributes to the phenotypic heterogeneity of the CD8+ T cell response but suggest that this process has a limited impact on memory populations at acute and chronic stages of infection.
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Project description:Durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a source for the pool of effector T cells, and in the absence of their cognate antigen, they are able to preserve their quantity through a process of self-renewal. However, it remains unknown how TCR engagement impacts the self-renewal capacity of Tpex in settings of continued antigen exposure. Here, we used a Lewis lung carcinoma model that elicits an optimal or attenuated TCR signal in CD8 T cells to investigate its effect on Tpex persistence during tumor development. Longitudinal phenotyping and single-cell transcriptomics of tumor-specific T cells revealed that formation of the Tpex reservoir in tumor-draining lymph nodes, and its subsequent replenishment of intratumoral Tpex, is dependent on optimal TCR engagement. Notably, adoptive transfer of optimally primed Tpex into a tumor setting with attenuated TCR stimulation significantly accelerates their terminal differentiation, contrasting to the sustained self-renewal occuring with optimal TCR stimulation. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cell niches and epigenetic imprinting that involves increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, our study highlights the critical role of TCR engagement in sustaining Tpex during tumor progression
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