A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation

Authors

• Dominic P. Golec, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Pedro H. Gazzinelli-Guimaraes, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Science, George Washington University, Washington, DC, USA.
• Daniel Chauss, Immunoregulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, USA.
• Kang Yu, Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD, USA.
• Hiroyuki Nagashima, Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD, USA.
• Anthony C. Cruz, Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD, USA.
• Tom Hill, National Institute of Allergy and Infectious Diseases Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Sundar Ganesan, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Jennifer L. Cannons, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Jillian K. Perry, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Luis Nivelo, Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
• Ilin Joshi, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Nicolas Pereira, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Fabrício Marcus Silva Oliveira, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Science, George Washington University, Washington, DC, USA.
• Yufan Zheng, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Makheni Jean Pierre, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Kirk M. Druey, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Justin B. Lack, National Institute of Allergy and Infectious Diseases Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Eric V. Dang, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Thomas B. Nutman, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
• Alejandro V. Villarino, Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
• John J. O'Shea, Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD, USA.
• Behdad Afzali, Immunoregulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, USA.
• Pamela L. Schwartzberg, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

4-6-2026

Journal

The Journal of experimental medicine

Volume

223

Issue

4

DOI

10.1084/jem.20252154

Abstract

While inputs regulating CD4+ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.

APA Citation

Golec, Dominic P.; Gazzinelli-Guimaraes, Pedro H.; Chauss, Daniel; Yu, Kang; Nagashima, Hiroyuki; Cruz, Anthony C.; Hill, Tom; Ganesan, Sundar; Cannons, Jennifer L.; Perry, Jillian K.; Nivelo, Luis; Joshi, Ilin; Pereira, Nicolas; Silva Oliveira, Fabrício Marcus; Zheng, Yufan; Jean Pierre, Makheni; Druey, Kirk M.; Lack, Justin B.; Dang, Eric V.; Nutman, Thomas B.; Villarino, Alejandro V.; O'Shea, John J.; Afzali, Behdad; and Schwartzberg, Pamela L., "A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4+ T cell signaling and differentiation" (2026). GW Authored Works. Paper 8657.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8657

Department

Microbiology, Immunology, and Tropical Medicine