title: Pak2 Links TCR Signaling Strength to the Development of Regulatory T Cells and Maintains Peripheral Tolerance.
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.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and.
authors.forename: Kyle Leonard
authors.initials: KL
authors.lastname: O'Hagan
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and.
authors.forename: Olga
authors.initials: O
authors.lastname: Pryshchep
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and hyewon.phee@northwestern.edu.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Phee
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D061166:Peripheral Tolerance / Q000235:genetics* / Q000276:immunology*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D054462:p21-Activated Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D054462:p21-Activated Kinases