TY - JOUR
T1 - Immune dysregulation in patients with PTEN hamartoma tumor syndrome
T2 - Analysis of FOXP3 regulatory T cells
AU - Chen, Hannah H.
AU - Händel, Norman
AU - Ngeow, Joanne
AU - Muller, James
AU - Hühn, Michael
AU - Yang, Huei Ting
AU - Heindl, Mario
AU - Berbers, Roos Marijn
AU - Hegazy, Ahmed N.
AU - Kionke, Janina
AU - Yehia, Lamis
AU - Sack, Ulrich
AU - Bläser, Frank
AU - Rensing-Ehl, Anne
AU - Reifenberger, Julia
AU - Keith, Julia
AU - Travis, Simon
AU - Merkenschlager, Andreas
AU - Kiess, Wieland
AU - Wittekind, Christian
AU - Walker, Lisa
AU - Ehl, Stephan
AU - Aretz, Stefan
AU - Dustin, Michael L.
AU - Eng, Charis
AU - Powrie, Fiona
AU - Uhlig, Holm H.
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - autoimmunity
KW - immunologic synapse
KW - PH domain leucine-rich repeat protein phosphatase
KW - phosphatases
KW - phosphoinositide 3-kinase
KW - PHTS
KW - PTEN
KW - Regulatory T cells
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U2 - 10.1016/j.jaci.2016.03.059
DO - 10.1016/j.jaci.2016.03.059
M3 - Article
C2 - 27477328
AN - SCOPUS:84979787965
SN - 0091-6749
VL - 139
SP - 607-620.e15
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -