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.

PTGER2-β-Catenin Axis Links High Salt Environments to Autoimmunity by Balancing IFNγ and IL-10 in FoxP3+Regulatory T cells

“…Of note, we also identified additional upstream regulators, either previously reported or of interest for future studies: MYB, SATB1, NFATC2, KLF2, ZBTB16 , and DDIT3 were all found to be significant upstream regulators across the Treg subpopulations. Treg-specific roles for MYB 33 , SATB1 34 , NFATC2 35 , and KLF2 36 have already been demonstrated in maintaining Treg functional properties, supporting the validity of our upstream regulator analysis. Given that these factors have a capacity to interact with β-catenin, for example, β-catenin can form a complex with SATB1 and modulate Th2 cell differentiation 62 , it is likely that these factors can interact to establish a complex regulatory system in Treg homeostasis.…”

“…Together, these results suggest that β-catenin plays a critical role in driving the production of both IFNγ and IL-10 in Tregs, especially for IFNγ. We also identified several upstream regulators that have been demonstrated to have critical roles in maintaining Treg function, including MYB 33 , SATB1 34 , NFATC2 35 , and KLF2 36 , suggesting that our upstream regulator analysis provides a reliable readout.…”

Suppression by human FOXP3 + regulatory T cells requires FOXP3-TIP60 interactions

“…Many of these genes, namely, NT5E, FOXO1, S1PR1, LGMN, KLF, DUSP5, and DUSP6, have been described to have a potential role in T reg development and function ( Fig. 3D) (22)(23)(24)(25)(26)(27)(28).…”

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

“…Alternatively, changes in the migration patterns of Tregs could explain this preferential enrichment in lymphoid tissues, because of the modulation of chemokines and adhesion molecules by statins (20, 37, 41). Remarkably, this Treg accumulation in lymphoid tissue could be critical for the establishment and regulation of an efficient antigen-specific immune response.…”