Peripheral tolerance can be modified by altering KLF2-regulated Treg migration.

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.

authors

Pabbisetty SK,Rabacal W,Volanakis EJ,Parekh VV,Olivares-Villagómez D,Cendron D,Boyd KL,Van Kaer L,Sebzda E

doi

10.1073/pnas.1605849113

subject

Has Abstract

pub_date

2016-08-09 00:00:00

pages

E4662-70

issue

32

eissn

0027-8424

issn

1091-6490

pii

1605849113

journal_volume

113

pub_type

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