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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

de Sio, Francesca R. Santoni¹  Passerini, Laura¹  Restelli, Silvia¹  Valente, Maria Maddalena¹  Pramov, Aleksandar²  Maccari, Maria Elena³  Sanvito, Francesca⁴  Roncarolo, Maria Grazia^5,6  Porteus, Matthew^5,6  Bacchetta, Rosa^1,5 

[1] San Raffaele Telethon Inst Gene Therapy, Milan, Italy

[2] IRCCS San Raffaele Sci Inst, Div Pathol, Milan, Italy

[3] San Raffaele Vita Salute Univ, Univ Ctr Stat Biomed Sci CUSSB, Milan, Italy

[4] San Raffaele Vita Salute Univ, Sch Med, Milan, Italy

[5] Stanford Sch Med, Dept Pediat, Div Stem Cell Transplantat & Regenerat Med, Stanford, CA USA

[6] Stanford Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA USA

关键词: Forkhead box P3;    effector T cells;    regulatory T cells;    immune tolerance;    humanized mice;    T-cell differentiation;    immune dysregulation;    polyendocrinopathy;    enteropathy;    X-linked syndrome;    autoimmunity;   

DOI  :  10.1016/j.jaci.2018.03.015

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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