Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis - 06/12/18
, Laura Passerini, PhD a, Silvia Restelli, BSc a, Maria Maddalena Valente, PhD a, Aleksandar Pramov, PhD b, Maria Elena Maccari, MD c, Francesca Sanvito, MD d, Maria Grazia Roncarolo, MD, PhD e, f, Matthew Porteus, MD, PhD e, f, Rosa Bacchetta, MD a, e, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Forkhead box P3, effector T cells, regulatory T cells, immune tolerance, humanized mice, T-cell differentiation, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, autoimmunity
Abbreviations used : APC, APECED, BM, ddPCR, FOXP3, HD, GAPDH, GFP, HPRT, HSPC, huMice, IPEX, KD, KO, LV, NHEJ, NPC, NSG, PB, PE, PerCP, shRNA, TALEN, TCR, Teff, TERF2, TREC, Treg, TSDR, TSS
Plan
| Supported by Telethon (Tele10-A4 to R.B.), Seventh Framework Project of the European Community (CellPID to R.B.), NIH-R21 (AI123896-01A1 to R.B.), and the Italian Ministry of Health (GR-2010-2317550 to F.R.S.d.S.). |
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| Disclosure of potential conflict of interest: M. Porteus reports personal fees and other from CRISPR Tx outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 6
P. 1909 - décembre 2018 Retour au numéro
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