Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo

David A. Horwitz, Stephanie Pan, Jing Ni Ou, Julie Wang, Maogen Chen, J. Dixon Gray, Song Guo Zheng

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-β. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/β, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft. versus-host disease, and allograft rejection.

Original languageEnglish (US)
Pages (from-to)450-463
Number of pages14
JournalClinical Immunology
Volume149
Issue number3 PB
DOIs
StatePublished - Dec 2013

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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