Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells

Hannah H. Chen, Norman Händel, Joanne Ngeow, James Muller, Michael Hühn, Huei Ting Yang, Mario Heindl, Roos Marijn Berbers, Ahmed N. Hegazy, Janina Kionke, Lamis Yehia, Ulrich Sack, Frank Bläser, Anne Rensing-Ehl, Julia Reifenberger, Julia Keith, Simon Travis, Andreas Merkenschlager, Wieland Kiess, Christian WittekindLisa Walker, Stephan Ehl, Stefan Aretz, Michael L. Dustin, Charis Eng, Fiona Powrie, Holm H. Uhlig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)607-620.e15
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number2
DOIs
Publication statusPublished - Feb 1 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 The Authors

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

Keywords

  • autoimmunity
  • immunologic synapse
  • PH domain leucine-rich repeat protein phosphatase
  • phosphatases
  • phosphoinositide 3-kinase
  • PHTS
  • PTEN
  • Regulatory T cells

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