Pak2 Links TCR Signaling Strength to the Development of Regulatory T Cells and Maintains Peripheral Tolerance

J Immunol. 2015 Aug 15;195(4):1564-77. doi: 10.4049/jimmunol.1500843. Epub 2015 Jul 8.

Abstract

Although significant effort has been devoted to understanding the thymic development of Foxp3(+) regulatory T cells (Tregs), the precise signaling pathways that govern their lineage commitment still remain enigmatic. Our findings show a novel role for the actin cytoskeletal remodeling protein, p21-activated kinase 2 (Pak2), in Treg development and homeostasis. The absence of Pak2 in T cells resulted in a marked reduction in both thymus- and peripherally derived Tregs, accompanied by the development of spontaneous colitis in Pak2-deficient mice. Additionally, Pak2 was required for the proper differentiation of in vitro-induced Tregs as well as maintenance of Tregs. Interestingly, Pak2 was necessary for generating the high-affinity TCR- and IL-2-mediated signals that are required by developing Tregs for their lineage commitment. These findings provide novel insight into how developing thymocytes translate lineage-specific high-affinity TCR signals to adopt the Treg fate, and they further posit Pak2 as an essential regulator for this process.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / pathology
  • Female
  • Forkhead Transcription Factors / metabolism
  • Homeostasis
  • Immunophenotyping
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Peripheral Tolerance / genetics*
  • Peripheral Tolerance / immunology*
  • Phenotype
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • p21-Activated Kinases / deficiency
  • p21-Activated Kinases / genetics*
  • p21-Activated Kinases / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • p21-Activated Kinases