Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4 + T cell perturbations

• Published in: Nature immunology Vol. 22; no. 5; pp. 607 - 619
• Main Authors: Zemmour, David, Charbonnier, Louis-Marie, Leon, Juliette, Six, Emmanuelle, Keles, Sevgi, Delville, Marianne, Benamar, Mehdi, Baris, Safa, Zuber, Julien, Chen, Karin, Neven, Benedicte, Garcia-Lloret, Maria I, Ruemmele, Frank M, Brugnara, Carlo, Cerf-Bensussan, Nadine, Rieux-Laucat, Frederic, Cavazzana, Marina, André, Isabelle, Chatila, Talal A, Mathis, Diane, Benoist, Christophe
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.05.2021
• Subjects: Adolescent; Animals; Autoimmunity; Bone marrow; Case-Control Studies; CD4 antigen; Cell activation; Child; Child, Preschool; Cohort Studies; Cytometry; Datasets as Topic; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - congenital; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diarrhea - blood; Diarrhea - genetics; Diarrhea - immunology; Disease Models, Animal; Flow Cytometry; Forkhead Transcription Factors - deficiency; Forkhead Transcription Factors - genetics; Foxp3 protein; Genetic Diseases, X-Linked - blood; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Homeostasis; Humans; Immune System Diseases - blood; Immune System Diseases - congenital; Immune System Diseases - genetics; Immune System Diseases - immunology; Infant; Interleukin 2; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Transgenic; Mutation; RNA-Seq; Single-Cell Analysis; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Young Adult
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-00910-8

FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (T ) cells. CD4 T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous T -like cells, some very similar to normal T cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4 T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal T cells exerted dominant suppression, quenching the disease signature and revealing in mutant T -like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes T cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering T cell dysfunction. Accordingly, interleukin-2 treatment improved the T -like compartment and survival.