Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.
Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.
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DOI：
10.1016/j.jaci.2016.03.059
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Uhlig HH
中科院分区：
文献类型：
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作者：
Chen HH;Händel N;Ngeow J;Muller J;Hühn M;Yang HT;Heindl M;Berbers RM;Hegazy AN;Kionke J;Yehia L;Sack U;Bläser F;Rensing-Ehl A;Reifenberger J;Keith J;Travis S;Merkenschlager A;Kiess W;Wittekind C;Walker L;Ehl S;Aretz S;Dustin ML;Eng C;Powrie F;Uhlig HH
10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）杂合种系突变的患者会发生自身免疫和淋巴样增生。由于磷酸肌醇3-激酶（PI 3 K）通路的调节对于维持调节性T细胞（Treg）功能至关重要，我们研究了杂合子生殖系PTEN突变（PTEN错构瘤肿瘤综合征[PHTS]）患者的Treg细胞。评估PHTS患者的免疫状况、淋巴细胞亚群、叉头盒P3（FOXP 3）+ Treg细胞水平和表型。为了确定控制PI 3 K通路的磷酸酶的功能重要性，我们评估了Treg细胞的体外诱导、线粒体去极化和PTEN向免疫突触的募集。在79例PHTS患者中，43%的患者存在自身免疫和外周淋巴组织增生。PHTS患者的免疫失调包括淋巴细胞减少、CD 4 + T细胞减少以及T和B细胞亚群的变化。虽然总的CD 4 + FOXP 3 + Treg细胞数量减少，但在血液和肠道中的频率保持不变。尽管存在致病性PTEN突变，但FOXP 3 + T细胞表型正常。我们发现，磷酸酶PH结构域富含亮氨酸重复蛋白磷酸酶（PHLPP）下游的PTEN是高度表达在正常的人Treg细胞，并提供互补的磷酸酶活性。PHLPP对于体外诱导的Treg细胞的分化和Treg细胞线粒体适应性是不可缺少的。PTEN和PHLPP形成在免疫突触处极化的磷酸酶网络。人类受试者中PTEN功能的杂合性丧失对T细胞和B细胞免疫具有显着影响。PTEN-PHLPP磷酸酶网络的组装允许在T细胞受体活化位点协调磷酸酶活性，这对于限制Treg细胞中的PI 3 K超活化是重要的，尽管PTEN单倍不足。
Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. 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]). 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. 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. 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.