AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.
Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1-Tregs. Using a genome-wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs. Furthermore, we describe the opposing roles of AKT isoforms in Th1-Treg generation ex vivo Finally, we employ multiple sclerosis as an in vivo model with increased but functionally defective Th1-Tregs. We show that the PI3K/AKT/Foxo1/3 pathway is activated in ex vivo-isolated Tregs from untreated relapsing-remitting MS patients and that blockade of the pathway inhibits IFNγ secretion and restores the immune suppressive function of Tregs. These data define a fundamental pathway regulating the function of human Tregs and suggest a novel treatment paradigm for autoimmune diseases.
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Alexandra
A
Kitz
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Marine
M
de Marcken
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Anne-Sophie
AS
Gautron
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Mitja
M
Mitrovic
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.
David A
DA
Hafler
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA margarita.dominguez-villar@yale.edu.
Margarita
0000-0002-9719-0028
M
Dominguez-Villar
D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D002454:Cell Differentiation; D016207:Cytokines; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D056747:Immunomodulation; D007371:Interferon-gamma / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D059467:Transcriptome
D015415:Biomarkers; D016207:Cytokines; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Foxp3; IFNγ; Tregs; autoimmunity; plasticity