التفاصيل البيبلوغرافية
| العنوان: |
Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells |
| المؤلفون: |
Chen, H, Handel, Ngeow, Huhn, Yang, Heindl, Berbers, Hegazy, A, Kionke, Yehia, Sack, Blaser, Rensing-Ehl, Reifenberger, Keith, J, Travis, S, Merkenschlager, Keiss, Wittekind, Walker, L, Ehl, Aretz, Dustin, Eng, Powrie, F, Uhlig, H |
| المصدر: |
The Journal of Allergy and Clinical Immunology |
| بيانات النشر: |
Elsevier BV, 2017. |
| سنة النشر: |
2017 |
| مصطلحات موضوعية: |
Male, PTEN, Immunological Synapses, TMRE, Tetramethylrhodamine-ethylester, T-Lymphocytes, Regulatory, SHIP, Src homology domain 2–containing inositol phosphatase, CS, Cowden syndrome, PI3K, Phosphoinositide 3-kinase, Phosphoprotein Phosphatases, Immunology and Allergy, phosphatases, Child, Cells, Cultured, MALT, Mucosa-associated lymphoid tissue, Membrane Potential, Mitochondrial, B-Lymphocytes, autoimmunity, phosphoinositide 3-kinase, Nuclear Proteins, PHLPP, PH domain leucine-rich repeat protein phosphatase, Forkhead Transcription Factors, POD, Peroxidase, Regulatory T cells, Middle Aged, IC50, Inhibitory concentration of 50%, FACS, Fluorescence-activated cell sorting, FOXP3, Forkhead box P3, Protein Transport, CTLA-4, Cytotoxic T lymphocyte–associated antigen 4, Protein Binding, Signal Transduction, Adult, FITC, Fluorescein isothiocyanate, PH domain leucine-rich repeat protein phosphatase, HRM, High Resolution DNA Melting, Adolescent, APC, Allophycocyanin, ICAM-1, Intercellular adhesion molecule 1, Immunology, NHERF1, Na+/H+-exchanger 3 regulatory factor, chemical and pharmacologic phenomena, mTORC1, PTEN/AKT/mTOR complex 1, DLG1, Scaffold protein discs, large homolog 1, PerCP, Peridinin-chlorophyll-protein complex, PP2A, Protein phosphatase 2A, immunologic synapse, Young Adult, Immune Deficiencies, Infection, and Systemic Immune Disorders, Humans, Aged, PTEN, Phosphatase and tensin homologue deleted on chromosome 10, Hyperplasia, PTEN Phosphohydrolase, mTOR, Mammalian target of rapamycin, PE, Phycoerythrin, PHTS, PTEN hamartoma tumor syndrome, Lymphocyte Subsets, TCR, T-cell receptor, Tmem, Memory T, iTreg, In vitro induced regulatory T, Mutation, PHTS, Hamartoma Syndrome, Multiple |
| الوصف: |
Background Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. Objectives Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). Methods Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. Results Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. Conclusion Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency.
Graphical abstract |
| تدمد: |
0091-6749 |
| DOI: |
10.1016/j.jaci.2016.03.059 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::7d641d886c66f79f3802609a220ac434 |
| Rights: |
OPEN |
| رقم الانضمام: |
edsair.pmid.dedup....7d641d886c66f79f3802609a220ac434 |
| قاعدة البيانات: |
OpenAIRE |