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The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program. scRNA-Seq profiling of mouse tissue Tregs with TCR sequencing and CITE-Seq

ABSTRACT: The tissues are the site of many important immunological reactions, yet how the immune system is controlled at these sites remains opaque. Recent studies have identified Foxp3+ regulatory T cells (Tregs) in non-lymphoid tissues, with unique characteristics compared to lymphoid Tregs. However, tissue Tregs have not been considered holistically across tissues. Here we performed a systematic analysis of the Treg population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency and common molecular dependencies. Tissue Tregs from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg entry, and were tissue-agnostic on tissue homing. Together these results demonstrate that the tissue-resident Treg pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Tregs, characterised by transient multi-tissue migration. This work suggests common regulatory mechanisms may allow pan-tissue Tregs to safeguard homeostasis across the body.

ORGANISM(S): Mus musculus

PROVIDER: GSE266111 | GEO | 2024/05/03

REPOSITORIES: GEO

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Project description:The first wave of Foxp3+ regulatory T cells (Tregs) generated in neonates has been reported to be indispensable for the life-long prevention of autoimmunity. Although it is widely accepted that neonates are highly susceptible to infections, the impact of neonatal infections on the first wave of Tregs is completely unknown. Here, we challenged newborn Treg fate-mapping mice (Foxp3eGFPCreERT2xRosa26-YFP) with the Toll-like receptor agonists LPS and poly I:C to mimic neonatal bacterial or viral infections, respectively, and subsequently administrated tamoxifen during the first eight days of life to selectively label the first wave of Tregs. Neonatally-tagged Tregs preferentially accumulated in non-lymphoid tissues when compared to lymphoid organs irrespective of the treatment. One week post perturbation, unexpectedly no differences in the frequency and phenotypes of neonatally-tagged Tregs were observed between challenged mice and untreated controls. However, upon aging, a decreased frequency of neonatally-tagged Tregs in both non-lymphoid tissues and lymphoid organs was detected in challenged mice when compared to untreated controls, and became significant twelve weeks post perturbation, with no signs of altered Foxp3 stability. Remarkably, this late decrease in the frequency of neonatally-tagged Tregs only occurred upon perturbations in newborns as challenging of eight-day-old mice did not result in long-lasting alterations of the first wave of Tregs. Combined single-cell T cell receptor (TCR)-seq and RNA-seq revealed that neonatal perturbations drastically diminished TCR diversity and long-lastingly altered the transcriptome of neonatally tagged Tregs, exemplified by lower expression of Tigit, Foxp3, and Il2ra. Together, our data demonstrate that a single, transient encounter with a pathogen in neonates can have long-lasting consequences for the first wave of Tregs, which might affect immunological tolerance, prevention of autoimmunity, and other non-canonical functions of tissue-resident Tregs.

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The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program. scRNA-Seq profiling of mouse tissue Tregs with TCR sequencing and CITE-Seq

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