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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states [RNA-Seq]

ABSTRACT: Assessment of transcriptional programs between TfhProg and TfhFull cells

ORGANISM(S): Mus musculus

PROVIDER: GSE225638 | GEO | 2023/10/20

REPOSITORIES: GEO

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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states.

Project description:Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production. We find that progression through these stages are controlled intrinsically by the transcription factor FoxP1 and extrinsically by follicular regulatory T cells. Through selective deletion of Tfh stages, we show that these cells control antibody dynamics during distinct stages of the germinal center reaction in response to a SARS-CoV-2 vaccine. Together, these studies demonstrate the sequential phases of Tfh development and how they promote humoral immunity.

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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states [RNA-Seq 2]

Project description:Assessment of transcriptional changes in TfhFull or TfhProg with FoxP1 deletion

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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states

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Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states [ATAC-Seq]

Project description:Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies. However, the signals that promote Tfh development after initial differentiation are unknown. Here we use fate mapping and reporter strategies to show that, after initial differentiation, Tfh cells transition from a progenitor-like Tfh (Tfh-Prog) stage to an IL-21-expressing fully developed Tfh (Tfh-Full) stage which is regulated by follicular regulatory T (Tfr) cells. Using single cell RNA sequencing and epigenomic analysis, we uncover additional developmental stages including an early Tfh transitory (Tfh-Trans) stage prior to full development, as well as an Tfh-Ex stage that occurs after full development marked by loss of IL-21 expression. The transcriptional and epigenetic landscape is formed in the Tfh-Transitory stage and is maintained throughout the Tfh-Ex state, suggesting terminal development. We also find the transcription factor Foxp1 regulates the transitions between these stages in Tfh cells to balance the ratio of stem-like progenitor and effector Tfh cells. Through selective in vivo deletion of Tfh-Full and Tfh-Ex cells, we show that these cells control antigen-specific germinal center formation, maintenance and somatic hypermutation at distinct stages of responses to a SARS-CoV-2 vaccine. Together, these studies demonstrate the transitionary phases of Tfh development and how control of the progression through these stages regulates humoral immunity.

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