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.
Subject(s)
Peripheral Tolerance/genetics , Peripheral Tolerance/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , p21-Activated Kinases/genetics , 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 , Phenotype , Signal Transduction , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/cytology , Thymus Gland/immunology , Thymus Gland/metabolism , p21-Activated Kinases/deficiency , p21-Activated Kinases/metabolismABSTRACT
The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR ß-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLCγ1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation.DOI: http://dx.doi.org/10.7554/eLife.02270.001.