PMID- 29705245 OWN - NLM STAT- MEDLINE DCOM- 20190913 LR - 20190913 IS - 1097-6825 (Electronic) IS - 0091-6749 (Linking) VI - 142 IP - 6 DP - 2018 Dec TI - Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. PG - 1909-1921.e9 LID - S0091-6749(18)30617-1 [pii] LID - 10.1016/j.jaci.2018.03.015 [doi] AB - BACKGROUND: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed. OBJECTIVE: We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology. METHODS: We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice). RESULTS: Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a T(H)2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels. CONCLUSIONS: These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome. CI - Copyright (c) 2018. Published by Elsevier Inc. FAU - Santoni de Sio, Francesca R AU - Santoni de Sio FR AD - San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: santonidesio.francesca@hsr.it. FAU - Passerini, Laura AU - Passerini L AD - San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. FAU - Restelli, Silvia AU - Restelli S AD - San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. FAU - Valente, Maria Maddalena AU - Valente MM AD - San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. FAU - Pramov, Aleksandar AU - Pramov A AD - University Center for Statistics in the Biomedical Sciences (CUSSB), San Raffaele Vita-Salute University, Milan, Italy. FAU - Maccari, Maria Elena AU - Maccari ME AD - School of Medicine, San Raffaele Vita-Salute University, Milan, Italy. FAU - Sanvito, Francesca AU - Sanvito F AD - Division of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy. FAU - Roncarolo, Maria Grazia AU - Roncarolo MG AD - Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, Calif; Institute of Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, Calif. FAU - Porteus, Matthew AU - Porteus M AD - Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, Calif; Institute of Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, Calif. FAU - Bacchetta, Rosa AU - Bacchetta R AD - San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, Calif. Electronic address: rosab@stanford.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180427 PL - United States TA - J Allergy Clin Immunol JT - The Journal of allergy and clinical immunology JID - 1275002 RN - 0 (FOXP3 protein, human) RN - 0 (Forkhead Transcription Factors) RN - Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome SB - IM EIN - J Allergy Clin Immunol. 2019 Mar;143(3):1269. PMID: 30850067 MH - Adolescent MH - Adult MH - Animals MH - Cell Differentiation MH - Child MH - Child, Preschool MH - Diabetes Mellitus, Type 1/*congenital/immunology MH - Diarrhea/*immunology MH - Forkhead Transcription Factors/*immunology MH - Genetic Diseases, X-Linked/*immunology MH - Homeostasis MH - Humans MH - Immune System Diseases/*congenital/immunology MH - Infant MH - Infant, Newborn MH - Male MH - Mice, Transgenic MH - T-Lymphocytes/*immunology MH - Thymus Gland/*immunology MH - Young Adult OTO - NOTNLM OT - Forkhead box P3 OT - T-cell differentiation OT - X-linked syndrome OT - autoimmunity OT - effector T cells OT - enteropathy OT - humanized mice OT - immune dysregulation OT - immune tolerance OT - polyendocrinopathy OT - regulatory T cells EDAT- 2018/05/01 06:00 MHDA- 2019/09/14 06:00 CRDT- 2018/04/30 06:00 PHST- 2017/02/28 00:00 [received] PHST- 2018/02/14 00:00 [revised] PHST- 2018/03/19 00:00 [accepted] PHST- 2018/05/01 06:00 [pubmed] PHST- 2019/09/14 06:00 [medline] PHST- 2018/04/30 06:00 [entrez] AID - S0091-6749(18)30617-1 [pii] AID - 10.1016/j.jaci.2018.03.015 [doi] PST - ppublish SO - J Allergy Clin Immunol. 2018 Dec;142(6):1909-1921.e9. doi: 10.1016/j.jaci.2018.03.015. Epub 2018 Apr 27.