Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis

FR Santoni de Sio, L Passerini, S Restelli, MM Valente, A Pramov, Maria Elena Maccari, F Sanvito, MG Roncarolo, M Porteus, R Bacchetta

Research output: Contribution to journalArticle

Abstract

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 TH2 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. © 2018
Original languageEnglish
Pages (from-to)1909-1921.e9
JournalJournal of Allergy and Clinical Immunology
Volume142
Issue number6
DOIs
Publication statusPublished - 2018

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Eragrostis
Homeostasis
T-Lymphocytes
Regulatory T-Lymphocytes
Thymocytes
T-Cell Antigen Receptor
Knockout Mice
Hematopoietic Stem Cells
Gene Knockdown Techniques
Hematopoietic System
Gene Knockout Techniques
Immune System
Transcription Factors
Pathology
Mutation
Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome

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Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. / Santoni de Sio, FR; Passerini, L; Restelli, S; Valente, MM; Pramov, A; Maccari, Maria Elena; Sanvito, F; Roncarolo, MG; Porteus, M; Bacchetta, R.

In: Journal of Allergy and Clinical Immunology, Vol. 142, No. 6, 2018, p. 1909-1921.e9.

Research output: Contribution to journalArticle

Santoni de Sio, FR, Passerini, L, Restelli, S, Valente, MM, Pramov, A, Maccari, ME, Sanvito, F, Roncarolo, MG, Porteus, M & Bacchetta, R 2018, 'Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis', Journal of Allergy and Clinical Immunology, vol. 142, no. 6, pp. 1909-1921.e9. https://doi.org/10.1016/j.jaci.2018.03.015
Santoni de Sio, FR ; Passerini, L ; Restelli, S ; Valente, MM ; Pramov, A ; Maccari, Maria Elena ; Sanvito, F ; Roncarolo, MG ; Porteus, M ; Bacchetta, R. / Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. In: Journal of Allergy and Clinical Immunology. 2018 ; Vol. 142, No. 6. pp. 1909-1921.e9.
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abstract = "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 TH2 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. {\circledC} 2018",
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T1 - Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis

AU - Santoni de Sio, FR

AU - Passerini, L

AU - Restelli, S

AU - Valente, MM

AU - Pramov, A

AU - Maccari, Maria Elena

AU - Sanvito, F

AU - Roncarolo, MG

AU - Porteus, M

AU - Bacchetta, R

PY - 2018

Y1 - 2018

N2 - 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 TH2 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. © 2018

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 TH2 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. © 2018

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DO - 10.1016/j.jaci.2018.03.015

M3 - Article

VL - 142

SP - 1909-1921.e9

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

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ER -