title: Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.
abstract: 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.
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Hannah H
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Händel
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY.
authors.forename: James
authors.initials: J
authors.lastname: Muller
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Hühn
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Heindl
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Roos-Marijn
authors.initials: RM
authors.lastname: Berbers
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Kionke
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lamis
authors.initials: L
authors.lastname: Yehia
authors.affiliation: Institute for Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sack
authors.affiliation: Institute for Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bläser
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre, Freiburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Department of Dermatology, Heinrich-Heine-University, Dusseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Reifenberger
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Keith
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Travis
authors.affiliation: Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Merkenschlager
authors.affiliation: Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Institute for Pathology, University of Leipzig, Leipzig, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Walker
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Centre, Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
authors.affiliation: Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Department of Pediatrics, University of Oxford, Oxford, United Kingdom. Electronic address: holm.uhlig@ndm.ox.ac.uk.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006965:Hyperplasia; D054992:Immunological Synapses / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PH domain leucine-rich repeat protein phosphatase; PHTS; PTEN; Regulatory T cells; autoimmunity; immunologic synapse; phosphatases; phosphoinositide 3-kinase