FOXP3 deficiency, from the mechanisms of the disease to curative strategies.
IPEX
TSDR
Treg cells
autoreactive B cells
autoreactive T cells
gene therapy
Journal
Immunological reviews
ISSN: 1600-065X
Titre abrégé: Immunol Rev
Pays: England
ID NLM: 7702118
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
pubmed:
23
11
2023
medline:
23
11
2023
entrez:
23
11
2023
Statut:
ppublish
Résumé
FOXP3 gene is a key transcription factor driving immune tolerance and its deficiency causes immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX), a prototypic primary immune regulatory disorder (PIRD) with defective regulatory T (Treg) cells. Although life-threatening, the increased awareness and early diagnosis have contributed to improved control of the disease. IPEX currently comprises a broad spectrum of clinical autoimmune manifestations from severe early onset organ involvement to moderate, recurrent manifestations. This review focuses on the mechanistic advancements that, since the IPEX discovery in early 2000, have informed the role of the human FOXP3+ Treg cells in controlling peripheral tolerance and shaping the overall immune landscape of IPEX patients and carrier mothers, contributing to defining new treatments.
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
244-258Informations de copyright
© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.
Références
Powell BR, Buist NR, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr. 1982;100(5):731-737. doi:10.1016/s0022-3476(82)80573-8
Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000;106(12):R75-R81. doi:10.1172/JCI11679
Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20-21. doi:10.1038/83713
Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18-20. doi:10.1038/83707
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-1061. doi:10.1126/science.1079490
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4(4):337-342. doi:10.1038/ni909
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330-336. doi:10.1038/ni904
Bacchetta R, Barzaghi F, Roncarolo MG. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci. 2018;1417(1):5-22. doi:10.1111/nyas.13011
Cepika AM, Sato Y, Liu JM, Uyeda MJ, Bacchetta R, Roncarolo MG. Tregopathies: monogenic diseases resulting in regulatory T-cell deficiency. J Allergy Clin Immunol. 2018;142(6):1679-1695. doi:10.1016/j.jaci.2018.10.026
Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020;5(49):eabb1662. doi:10.1126/sciimmunol.abb1662
Chan AY, Torgerson TR. Primary immune regulatory disorders: a growing universe of immune dysregulation. Curr Opin Allergy Clin Immunol. 2020;20(6):582-590. doi:10.1097/aci.0000000000000689
Bousfiha A, Moundir A, Tangye SG, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022;42(7):1508-1520. doi:10.1007/s10875-022-01352-z
Barzaghi F, Amaya Hernandez LC, Neven B, et al. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. 2018;141(3):1036-1049. doi:10.1016/j.jaci.2017.10.041
Gambineri E, Ciullini Mannurita S, Hagin D, et al. Clinical, immunological, and molecular heterogeneity of 173 patients with the phenotype of immune dysregulation, Polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Front Immunol. 2018;9:2411. doi:10.3389/fimmu.2018.02411
Duclaux-Loras R, Charbit-Henrion F, Neven B, et al. Clinical heterogeneity of immune dysregulation, Polyendocrinopathy, enteropathy, X-linked syndrome: a French multicenter retrospective study. Clin Transl Gastroenterol. 2018;9:e201.
Consonni F, Ciullini Mannurita S, Gambineri E. Atypical presentations of IPEX: expect the unexpected. Front Pediatr. 2021;9(40):643094. doi:10.3389/fped.2021.643094
Sheikine Y, Woda CB, Lee PY, et al. Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. Pediatr Nephrol. 2015;30(7):1197-1202. doi:10.1007/s00467-015-3102-x
Miller P, Lei L, Charu V, Higgins J, Troxell M, Kambham N. Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population. Pediatr Nephrol. 2022;37(12):3127-3137. doi:10.1007/s00467-022-05503-7
Huang G, Liu F, Yu L, Wang J, Chen J, Mao J. Pediatric membranous nephropathy: in the novel antigens era. Front Immunol. 2022;13:962502. doi:10.3389/fimmu.2022.962502
Park JH, Lee KH, Jeon B, et al. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: a systematic review. Autoimmun Rev. 2020;19(6):102526. doi:10.1016/j.autrev.2020.102526
Jamee M, Zaki-Dizaji M, Lo B, et al. Clinical, immunological, and genetic features in patients with immune dysregulation, Polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome. J Allergy Clin Immunol Pract. 2020;8(8):2747-2760.e7. doi:10.1016/j.jaip.2020.04.070
Narula M, Lakshmanan U, Borna S, et al. Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation. J Allergy Clin Immunol. 2023;151(1):233-246.e10. doi:10.1016/j.jaci.2022.09.013
Mailer RK. IPEX as a consequence of alternatively spliced FOXP3. Front Pediatr. 2020;8:594375. doi:10.3389/fped.2020.594375
Frith K, Joly AL, Ma CS, et al. The FOXP3Δ2 isoform supports Treg cell development and protects against severe IPEX syndrome. J Allergy Clin Immunol. 2019;144(1):317-320.e8. doi:10.1016/j.jaci.2019.03.003
Magg T, Wiebking V, Conca R, et al. IPEX due to an exon 7 skipping FOXP3 mutation with autoimmune diabetes mellitus cured by selective T(Reg) cell engraftment. Clin Immunol. 2018;191:52-58. doi:10.1016/j.clim.2018.03.008
Chen CA, Chung WC, Chiou YY, et al. Quantitative analysis of tissue inflammation and responses to treatment in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and review of literature. J Microbiol Immunol Infect. 2016;49(5):775-782. doi:10.1016/j.jmii.2015.10.015
Borna S, Lee E, Nideffer J, et al. Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Sci Transl Med. 2023. in Press. doi:10.1126/scitranslmed.adg6822
Kinnunen T, Chamberlain N, Morbach H, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013;121(9):1595-1603. doi:10.1182/blood-2012-09-457465
Zemmour D, Charbonnier LM, Leon J, et al. Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4(+) T cell perturbations. Nat Immunol. 2021;22(5):607-619. doi:10.1038/s41590-021-00910-8
Santoni de Sio FR, Passerini L, Restelli S, et al. Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. J Allergy Clin Immunol. 2018;142(6):1909-1921 e9. doi:10.1016/j.jaci.2018.03.015
Passerini L, Olek S, Di Nunzio S, et al. Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability. J Allergy Clin Immunol. 2011;128(6):1376-1379 e1. doi:10.1016/j.jaci.2011.09.010
d'Hennezel E, Ben-Shoshan M, Ochs HD, et al. FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. N Engl J Med. 2009;361(17):1710-1713. doi:10.1056/NEJMc0907093
Tripathi D, Kant S, Pandey S, Ehtesham NZ. Resistin in metabolism, inflammation, and disease. FEBS J. 2020;287(15):3141-3149. doi:10.1111/febs.15322
Huang Y, Fang S, Zeng T, et al. Clinical and immunological characteristics of five patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China-expanding the atypical phenotypes. Front Immunol. 2022;13:972746. doi:10.3389/fimmu.2022.972746
McMurchy AN, Gillies J, Allan SE, et al. Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked have diverse abilities to reprogram T cells into regulatory T cells. J Allergy Clin Immunol. 2010;126(6):1242-1251. doi:10.1016/j.jaci.2010.09.001
Passerini L, Barzaghi F, Curto R, et al. Treatment with rapamycin can restore regulatory T-cell function in IPEX patients. J Allergy Clin Immunol. 2020;145(4):1262-1271 e13. doi:10.1016/j.jaci.2019.11.043
Marson A, Kretschmer K, Frampton GM, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445(7130):931-935. doi:10.1038/nature05478
Camperio C, Caristi S, Fanelli G, Soligo M, Del Porto P, Piccolella E. Forkhead transcription factor FOXP3 upregulates CD25 expression through cooperation with RelA/NF-κB. PLoS One. 2012;7(10):e48303. doi:10.1371/journal.pone.0048303
Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006;126(2):375-387. doi:10.1016/j.cell.2006.05.042
Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116(6):1713-1722. doi:10.1172/JCI25112
Goodwin M, Lee E, Lakshmanan U, et al. CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells. Sci Adv. 2020;6(19):eaaz0571. doi:10.1126/sciadv.aaz0571
Charbonnier LM, Cui Y, Stephen-Victor E, et al. Functional reprogramming of regulatory T cells in the absence of Foxp3. Nat Immunol. 2019;20(9):1208-1219. doi:10.1038/s41590-019-0442-x
Wyatt RC, Olek S, De Franco E, et al. FOXP3 TSDR measurement could assist variant classification and diagnosis of IPEX syndrome. J Clin Immunol. 2023;43(3):662-669. doi:10.1007/s10875-022-01428-w
Barzaghi F, Passerini L, Gambineri E, et al. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012;38(1):49-58. doi:10.1016/j.jaut.2011.12.009
Floess S, Freyer J, Siewert C, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2):e38. doi:10.1371/journal.pbio.0050038
Baron U, Floess S, Wieczorek G, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007;37(9):2378-2389. doi:10.1002/eji.200737594
Baron U, Werner J, Schildknecht K, et al. Epigenetic immune cell counting in human blood samples for immunodiagnostics. Sci Transl Med. 2018;10(452):eaan3508. doi:10.1126/scitranslmed.aan3508
Shamriz O, Patel K, Marsh RA, et al. Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome. Clin Immunol. 2018;197:219-223. doi:10.1016/j.clim.2018.10.005
Tsuda M, Torgerson TR, Selmi C, et al. The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies. J Autoimmun. 2010;35(3):265-268. doi:10.1016/j.jaut.2010.06.017
Hoshino A, Kanegane H, Nishi M, et al. Identification of autoantibodies using human proteome microarrays in patients with IPEX syndrome. Clin Immunol. 2019;203:9-13. doi:10.1016/j.clim.2019.03.011
Lampasona V, Passerini L, Barzaghi F, et al. Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome. PLoS One. 2013;8(11):e78664. doi:10.1371/journal.pone.0078664
Kobayashi I, Kubota M, Yamada M, et al. Autoantibodies to villin occur frequently in IPEX, a severe immune dysregulation, syndrome caused by mutation of FOXP3. Clin Immunol. 2011;141(1):83-89. doi:10.1016/j.clim.2011.05.010
Chida N, Kobayashi I, Takezaki S, et al. Disease specificity of anti-tryptophan hydroxylase-1 and anti-AIE-75 autoantibodies in APECED and IPEX syndrome. Clin Immunol. 2015;156(1):36-42. doi:10.1016/j.clim.2014.10.010
Eriksson D, Bacchetta R, Gunnarsson HI, et al. The autoimmune targets in IPEX are dominated by gut epithelial proteins. J Allergy Clin Immunol. 2019;144(1):327-330.e8. doi:10.1016/j.jaci.2019.02.031
Vazquez SE, Mann SA, Bodansky A, et al. Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq. elife. 2022;11:e78550. doi:10.7554/eLife.78550
Rosenberg JM, Maccari ME, Barzaghi F, et al. Neutralizing anti-cytokine autoantibodies against interferon-α in Immunodysregulation Polyendocrinopathy enteropathy X-linked. Front Immunol. 2018;9:544. doi:10.3389/fimmu.2018.00544
Li MO, Rudensky AY. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol. 2016;16(4):220-233. doi:10.1038/nri.2016.26
Stadinski BD, Shekhar K, Gomez-Tourino I, et al. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat Immunol. 2016;17(8):946-955. doi:10.1038/ni.3491
Lee HM, Bautista JL, Scott-Browne J, Mohan JF, Hsieh CS. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity. 2012;37(3):475-486. doi:10.1016/j.immuni.2012.07.009
Lam AJ, Lin DTS, Gillies JK, et al. Optimized CRISPR-mediated gene knockin reveals FOXP3-independent maintenance of human Treg identity. Cell Rep. 2021;36(5):109494. doi:10.1016/j.celrep.2021.109494
Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569-581. doi:10.1016/j.immuni.2014.02.012
Boschetti G, Sarfati M, Fabien N, et al. Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3(+) T cells in a patient with IPEX syndrome. Joint Bone Spine. 2020;87(5):483-486. doi:10.1016/j.jbspin.2020.04.013
Maher MC, Hall EM, Horii KA. Generalized eczematous dermatitis and pruritus responsive to dupilumab in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Pediatr Dermatol. 2021;38(5):1370-1371. doi:10.1111/pde.14717
Newton R, Priyadharshini B, Turka LA. Immunometabolism of regulatory T cells. Nat Immunol. 2016;17(6):618-625. doi:10.1038/ni.3466
Angelin A, Gil-de-Gómez L, Dahiya S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25(6):1282-1293.e7. doi:10.1016/j.cmet.2016.12.018
Di Nunzio S, Cecconi M, Passerini L, et al. Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood. 2009;114(19):4138-4141. doi:10.1182/blood-2009-04-214593
Tommasini A, Ferrari S, Moratto D, et al. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin Exp Immunol. 2002;130(1):127-130. doi:10.1046/j.1365-2249.2002.01940.x
Otsubo K, Kanegane H, Kamachi Y, et al. Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Immunol. 2011;141(1):111-120. doi:10.1016/j.clim.2011.06.006
Seidel MG, Fritsch G, Lion T, et al. Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113(22):5689-5691. doi:10.1182/blood-2009-02-206359
Kasow KA, Morales-Tirado VM, Wichlan D, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol. 2011;141(2):169-176. doi:10.1016/j.clim.2011.07.005
Katz G, Voss K, Yan TF, et al. FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression. Cell Immunol. 2018;327:54-61. doi:10.1016/j.cellimm.2018.02.007
Allan SE, Crome SQ, Crellin NK, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19(4):345-354. doi:10.1093/intimm/dxm014
McMurchy AN, Gillies J, Gizzi MC, et al. A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood. 2013;121(8):1265-1275. doi:10.1182/blood-2012-05-431023
Voss K, Lake C, Luthers CR, et al. FOXP3 protects conventional human T cells from premature restimulation-induced cell death. Cell Mol Immunol. 2021;18(1):194-205. doi:10.1038/s41423-019-0316-z
Nieves DS, Phipps RP, Pollock SJ, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol. 2004;140(4):466-472. doi:10.1001/archderm.140.4.466
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science. 2003;301(5638):1374-1377. doi:10.1126/science.1086907
Meffre E, O'Connor KC. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol Rev. 2019;292(1):90-101. doi:10.1111/imr.12821
Chen JW, Rice TA, Bannock JM, et al. Autoreactivity in naïve human fetal B cells is associated with commensal bacteria recognition. Science. 2020;369(6501):320-325. doi:10.1126/science.aay9733
Sng J, Ayoglu B, Chen JW, et al. AIRE expression controls the peripheral selection of autoreactive B cells. Sci Immunol. 2019;4(34):eaav6778. doi:10.1126/sciimmunol.aav6778
Hervé M, Isnardi I, Ng YS, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. 2007;204(7):1583-1593. doi:10.1084/jem.20062287
Janssen E, Morbach H, Ullas S, et al. Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin Immunol. 2014;134(6):1365-1374. doi:10.1016/j.jaci.2014.07.042
Pala F, Morbach H, Castiello MC, et al. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest. 2015;125(10):3941-3951. doi:10.1172/jci82249
Massaad MJ, Zhou J, Tsuchimoto D, et al. Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. J Clin Invest. 2016;126(11):4219-4236. doi:10.1172/jci85647
Chen JW, Schickel JN, Tsakiris N, et al. Positive and negative selection shape the human naive B cell repertoire. J Clin Invest. 2022;132(2):e150985. doi:10.1172/jci150985
Sauer AV, Morbach H, Brigida I, Ng YS, Aiuti A, Meffre E. Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy. J Clin Invest. 2012;122(6):2141-2152. doi:10.1172/jci61788
Hayatsu N, Miyao T, Tachibana M, et al. Analyses of a mutant Foxp3 allele reveal BATF as a critical transcription factor in the differentiation and accumulation of tissue regulatory T cells. Immunity. 2017;47(2):268-283.e9. doi:10.1016/j.immuni.2017.07.008
Van Gool F, Nguyen MLT, Mumbach MR, et al. A mutation in the transcription factor Foxp3 drives T helper 2 effector function in regulatory T cells. Immunity. 2019;50(2):362-377. doi:10.1016/j.immuni.2018.12.016
Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445(7129):766-770. doi:10.1038/nature05479
Leon J, Chowdhary K, Zhang W, et al. Mutations from patients with IPEX ported to mice reveal different patterns of FoxP3 and Treg dysfunction. Cell Rep. 2023;42(8):113018. doi:10.1016/j.celrep.2023.113018
Bin Dhuban K, d'Hennezel E, Nagai Y, et al. Suppression by human FOXP3(+) regulatory T cells requires FOXP3-TIP60 interactions. Sci Immunol. 2017;2(12):eaai9297. doi:10.1126/sciimmunol.aai9297
An YF, Xu F, Wang M, Zhang ZY, Zhao XD. Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China. Scand J Immunol. 2011;74(3):304-309. doi:10.1111/j.1365-3083.2011.02574.x
Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12):4743-4748. doi:10.1182/blood-2004-10-3932
Monti P, Scirpoli M, Maffi P, et al. Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells. Diabetes. 2008;57(9):2341-2347. doi:10.2337/db08-0138
Shah RM, Elfeky R, Nademi Z, et al. T-cell receptor αβ(+) and CD19(+) cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. J Allergy Clin Immunol. 2018;141(4):1417-1426.e1. doi:10.1016/j.jaci.2017.07.008
Merli P, Pagliara D, Galaverna F, et al. TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders. Blood Adv. 2022;6(1):281-292. doi:10.1182/bloodadvances.2021005628
Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov. 2019;18(10):749-769. doi:10.1038/s41573-019-0041-4
Allan SE, Alstad AN, Merindol N, et al. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther. 2008;16(1):194-202. doi:10.1038/sj.mt.6300341
Passerini L, Rossi Mel E, Sartirana C, et al. CD4(+) T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013;5(215):215ra174. doi:10.1126/scitranslmed.3007320
Sato Y, Passerini L, Piening BD, et al. Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo. Clin Transl Immunol. 2020;9(11):e1214. doi:10.1002/cti2.1214
Santoni de Sio FR, Passerini L, Valente MM, et al. Ectopic FOXP3 expression preserves primitive features of human hematopoietic stem cells while impairing functional T cell differentiation. Sci Rep. 2017;7(1):15820. doi:10.1038/s41598-017-15689-8
Sato Y, Liu J, Lee E, Perriman R, Roncarolo MG, Bacchetta R. Co-expression of FOXP3FL and FOXP3Δ2 isoforms is required for optimal Treg-like cell phenotypes and suppressive function. Front Immunol. 2021;12(4184):752394. doi:10.3389/fimmu.2021.752394
Masiuk KE, Laborada J, Roncarolo MG, Hollis RP, Kohn DB. Lentiviral gene therapy in HSCs restores lineage-specific Foxp3 expression and suppresses autoimmunity in a mouse model of IPEX syndrome. Cell Stem Cell. 2019;24(2):309-317. doi:10.1016/j.stem.2018.12.003