Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells

W. Ge, J. Jiang, W. Liu, D. Lian, A. Saito, B. Garcia, X. C. Li, H. Wang

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40+CD44 hieffector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (α-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, α-OX40L was added to the combined treatment protocol of LF15-0195 (LF) and anti-CD45RB (α-CD45RB) mAb - a protocol that induced heart allograft tolerance in non-presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor-specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4+CD25 +Foxp3+ T regulatory cells (Tregs). Of note, CD25 + T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor-primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance.

Original languageEnglish (US)
Pages (from-to)1760-1773
Number of pages14
JournalAmerican Journal of Transplantation
Volume10
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • Allograft tolerance
  • memory T cells
  • regulatory T cells
  • sensitized recipients
  • transplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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