Peripheral Tolerance Can Be Modified by Altering KLF2-regulated Treg Migration

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Jul 28

PMID 27462110

Citations 18

Authors

Sudheer K Pabbisetty

Whitney Rabacal

Emmanuel J Volanakis

Vrajesh V Parekh

Danyvid Olivares-Villagomez

Delphine Cendron

Kelli L Boyd

Luc Van Kaer

Eric Sebzda

Affiliations

Soon will be listed here.

Abstract

Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.

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