Coordinated involvement of cathepsins S, D and cystatin C in the commitment of hematopoietic stem cells to dendritic cells

Sabata Martino, Roberto Tiribuzi, Elisa Ciraci, Georgia Makrypidi, Francesco D'Angelo, Ilaria Di Girolamo, Angela Gritti, Gabriella M Cusella De Angelis, Gianpaolo Papaccio, Maurilio Sampaolesi, Anna Concetta Berardi, Alessandro Datti, Aldo Orlacchio

Research output: Contribution to journalArticlepeer-review

Abstract

The identity of biochemical players which underpin the commitment of CD34+ hematopoietic stem cells to immunogenic or tolerogenic dendritic cells is largely unknown. To explore this issue, we employed a previously established cell-based system amenable to shift dendritic cell differentiation from the immunogenic into the tolerogenic pathway upon supplementation with a conventional cytokine cocktail containing thrombopoietin (TPO) and IL-16. We show that stringent regulation of cathepsins S and D, two proteases involved in antigen presentation, is crucial to engage cell commitment to either route. In response to TPO + IL-16-dependent signaling, both cathepsins undergo earlier maturation and down-regulation. Additionally, cystatin C orchestrates cathepsin S expression through a tight but reversible interaction that, based on a screen of adult stem cells from disparate origins, CD14+ cells, primary fibroblasts and the MCF7 cell line, appears unique to CD34+ stem cells from peripheral and cord blood. As shown by CD4+ T cell proliferation in mixed-lymphocyte reactions, cell commitment to either pathway is disrupted upon cathepsin knockdown by RNAi. Surprisingly, similar effects were also observed upon gene overexpression, which prompts atypically accelerated maturation of cathepsins S and D in cells of the immunogenic pathway, similar to the tolerogenic route. Furthermore, RNAi studies revealed that cystatin C is a proteolytic target of cathepsin D and has a direct, causal impact on cell differentiation. Together, these findings uncover a novel biochemical cluster that is subject to time-controlled and rigorously balanced expression to mediate specific stem cell commitment at the crossroads towards tolerance or immunity.

Original languageEnglish
Pages (from-to)775-783
Number of pages9
JournalInternational Journal of Biochemistry and Cell Biology
Volume43
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • Cathepsin
  • Commitment
  • Cystatin C
  • Dendritic cell
  • Hematopoietic stem cell

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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