FOXP3 and Tip60 Structural Interactions Relevant to IPEX Development Lead to Potential Therapeutics to Increase FOXP3 Dependent Suppressor T Cell Functions.

Payal Grover,Mark I Greene,Peeyush N Goel,Ciriaco A Piccirillo

doi:10.3389/fped.2021.607292

Payal Grover, Mark I Greene + Show 2 more

Open Access

https://doi.org/10.3389/fped.2021.607292

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Abstract

Regulatory T (Treg) cells play a role in the maintenance of immune homeostasis and are critical mediators of immune tolerance. The Forkhead box P3 (FOXP3) protein acts as a regulator for Treg development and function. Mutations in the FOXP3 gene can lead to autoimmune diseases such as Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome in humans, often resulting in death within the first 2 years of life and a scurfy like phenotype in Foxp3 mutant mice. We discuss biochemical features of the FOXP3 ensemble including its regulation at various levels (epigenetic, transcriptional, and post-translational modifications) and molecular functions. The studies also highlight the interactions of FOXP3 and Tat-interacting protein 60 (Tip60), a principal histone acetylase enzyme that acetylates FOXP3 and functions as an essential subunit of the FOXP3 repression ensemble complex. Lastly, we have emphasized the role of allosteric modifiers that help stabilize FOXP3:Tip60 interactions and discuss targeting this interaction for the therapeutic manipulation of Treg activity.

Highlights

Specialty section: This article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics
IPEX is caused by mutations in the human Forkhead box P3 (FOXP3) gene that normally influences the function of T regulatory (Treg) cells [2,3,4]
FOXP3 interacts with nuclear factor of activated T cells (NFAT) to suppress the expression of inflammatory genes IL-2 and IFN-γ while functioning as a transcriptional activator of Treg cells by enhancing the gene expression of CD25, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and glucocorticoid-induced TNF receptor (GITR) [47,48,49,50]

Summary

Introduction

Specialty section: This article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics. IPEX is caused by mutations in the human FOXP3 gene that normally influences the function of T regulatory (Treg) cells [2,3,4]. FOXP3 is the master regulator for the development and function of regulatory T cells or Treg that are one of key mediators of immune tolerance and homeostasis.

Results

Conclusion