title: 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.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Sudheer K
authors.initials: SK
authors.lastname: Pabbisetty
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Whitney
authors.initials: W
authors.lastname: Rabacal
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Volanakis
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Vrajesh V
authors.initials: VV
authors.lastname: Parekh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Danyvid
authors.initials: D
authors.lastname: Olivares-Villagómez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Delphine
authors.initials: D
authors.lastname: Cendron
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; eric.sebzda@vanderbilt.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Sebzda
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002465:Cell Movement; D007108:Immune Tolerance; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D016201:Receptors, Lymphocyte Homing
keywords: KLF2; Treg migration; autoimmunity; peripheral tolerance; regulatory T cell