IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes

Elena Boggio, Nausicaa Clemente, Anna Mondino, Giuseppe Cappellano, Elisabetta Orilieri, Casimiro L. Gigliotti, Erika Toth, Ugo Ramenghi, Umberto Dianzani, Annalisa Chiocchetti

Research output: Contribution to journalArticle

Abstract

In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αβ+ CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD.

Original languageEnglish
Pages (from-to)1178-1186
Number of pages9
JournalBlood
Volume123
Issue number8
DOIs
Publication statusPublished - Feb 20 2014

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Boggio, E., Clemente, N., Mondino, A., Cappellano, G., Orilieri, E., Gigliotti, C. L., Toth, E., Ramenghi, U., Dianzani, U., & Chiocchetti, A. (2014). IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes. Blood, 123(8), 1178-1186. https://doi.org/10.1182/blood-2013-07-518167