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Activated PI3Kδ Specifically Perturbs Mouse Regulatory T Cell Homeostasis and Function Leading to Immune Dysregulation.
Singh, Akhilesh K; Al Qureshah, Fahd; Drow, Travis; Hou, Baidong; Rawlings, David J.
Affiliation
  • Singh AK; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
  • Al Qureshah F; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
  • Drow T; Department of Immunology, University of Washington, Seattle, WA.
  • Hou B; Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
  • Rawlings DJ; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
J Immunol ; 213(2): 135-147, 2024 07 15.
Article in En | MEDLINE | ID: mdl-38829130
ABSTRACT
FOXP3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3Kδ is required for normal Treg development and function. However, the impacts of dysregulated PI3Kδ signaling on Treg function remain incompletely understood. In this study, we used a conditional mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the Treg compartment. Activated mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation, as demonstrated by increased memory/effector CD4+ and CD8+ T cells with enhanced IFN-γ secretion, spontaneous germinal center responses, and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype, including increased PD-1 expression and reduced competitive fitness. Consistent with these findings, Treg-specific aPIK3CD mice mounted an elevated humoral response following immunization with a T cell-dependent Ag, which correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3Kδ activity is critical for Treg homeostasis and function, suggesting that PI3Kδ signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes, Regulatory / Class I Phosphatidylinositol 3-Kinases / Homeostasis Limits: Animals Language: En Journal: J Immunol / J. immunol / Journal of immunology Year: 2024 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes, Regulatory / Class I Phosphatidylinositol 3-Kinases / Homeostasis Limits: Animals Language: En Journal: J Immunol / J. immunol / Journal of immunology Year: 2024 Type: Article