Treatment with rapamycin can restore regulatory T-cell function in IPEX patients

Laura Passerini, Federica Barzaghi, Rosalia Curto, Claudia Sartirana, Graziano Barera, Francesca Tucci, Luca Albarello, Alberto Mariani, Pier Alberto Testoni, Elena Bazzigaluppi, Emanuele Bosi, Vito Lampasona, Olaf Neth, Daniele Zama, Manfred Hoenig, Ansgar Schulz, Markus G. Seidel, Ivana Rabbone, Sven Olek, Maria G. RoncaroloMaria P. Cicalese, Alessandro Aiuti, Rosa Bacchetta

Research output: Contribution to journalArticlepeer-review


Background: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. Objective: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. Methods: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. Results: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients’ Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. Conclusions: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Original languageEnglish
Pages (from-to)1262-1271.e13
JournalJournal of Allergy and Clinical Immunology
Issue number4
Publication statusPublished - Apr 2020


  • autoimmunity
  • Ebi3
  • FOXP3
  • GITR
  • IPEX
  • mTOR
  • rapamycin
  • regulatory T cells
  • suppression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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