decoding foxp3's code | Masahiro Ono

This blog introduces a new model for Foxp3 and Treg proposed in Ono et al., 2020 (Ono, 2020).

Introduction:

Foxp3 is essential for the differentiation and function of regulatory T cells (Tregs). A deeper understanding of how Foxp3 operates is crucial for comprehending its role in T cell regulation.

Key Insights:

The paper posits that Foxp3 interacts with crucial proteins to execute its regulatory functions. Specifically, Foxp3 partners with transcription factors that are downstream of T cell receptor (TCR) signaling. This interaction is key to understanding how Tregs, which are characterized as ‘self-reactive,’ depend on TCR signaling for their survival and functionality. These concepts will be expanded upon in future discussions.

New Model:

Foxp3 provides ‘long-range’ negative feedback to T cell activities, transcending simple suppression of TCR signaling. Instead, it modifies the outcomes of downstream TCR signaling activities. In this context, a set of crucial Foxp3-interacting transcription factors, particularly Runx1, plays pivotal roles. Runx1 binds to essential genomic regions, thereby enabling Foxp3 to effectively modulate T cell functions, predominantly the suppressive actions of Tregs.

A model for Foxp3-mediated control of the basal state and TCR-driven transcirptional regulation.

The exploration of these interactions offers significant insights at both the molecular and cellular levels regarding Foxp3’s function and the activation, differentiation, and function of Tregs.

Conclusion:

These findings support a model in which Foxp3 not only alters the basal state of T cell transcriptional regulation but also the consequences of TCR signaling within the nucleus. This capability is essential for T cells to adapt their baseline behavior and modify their functional outputs during activation.

The proposed model underscores the critical foundation of Treg and Foxp3, as encapsulated in the title “Control of Regulatory T‐cell Differentiation and Function by T‐Cell Receptor Signalling and Foxp3 Transcription Factor Complexes.”

References

2020

Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes

Masahiro Ono

Immunology, May 2020

Abstract Publication

Summary The transcription factor Foxp3 controls the differentiation and function of regulatory T-cells (Treg). Studies in the past decades identified numerous Foxp3-interacting protein partners. However, it is still not clear how Foxp3 produces the Treg-type transcriptomic landscape through cooperating with its partners. Here I show the current understanding of how Foxp3 transcription factor complexes regulate the differentiation, maintenance and functional maturation of Treg. Importantly, T-cell receptor (TCR) signalling plays central roles in Treg differentiation and Foxp3-mediated gene regulation. Differentiating Treg will have recognized their cognate antigens and received TCR signals before initiating Foxp3 transcription, which is triggered by TCR-induced transcription factors including NFAT, AP-1 and NF-κB. Once expressed, Foxp3 seizes TCR signal-induced transcriptional and epigenetic mechanisms through interacting with AML1/Runx1 and NFAT. Thus, Foxp3 modifies gene expression dynamics of TCR-induced genes, which constitute cardinal mechanisms for Treg-mediated immune suppression. Next, I discuss the following key topics, proposing new mechanistic models for Foxp3-mediated gene regulation: (i) how Foxp3 transcription is induced and maintained by the Foxp3-inducing enhanceosome and the Foxp3 autoregulatory transcription factor complex; (ii) molecular mechanisms for effector Treg differentiation (i.e. Treg maturation); (iii) how Foxp3 activates or represses its target genes through recruiting coactivators and corepressors; (iv) the ‘decision-making’ Foxp3-containing transcription factor complex for Th17 and Treg differentiation; and (v) the roles of post-translational modification in Foxp3 regulation. Thus, this article provides cutting-edge understanding of molecular biology of Foxp3 and Treg, integrating findings by biochemical and genomic studies.