Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Xueli Yuan, Mohammed Javeed I Ansari, Francesca D'Addio, Jesus Paez-Cortez, Isabella Schmitt, Michela Donnarumma, Olaf Boenisch, Xiaozhi Zhao, Joyce Popoola, Michael R. Clarkson, Hideo Yagita, Hisaya Akiba, Gordon J. Freeman, John Iacomini, Laurence A. Turka, Laurie H. Glimcher, Mohamed H. Sayegh

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.

Original languageEnglish (US)
Pages (from-to)10734-10739
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number26
DOIs
Publication statusPublished - Jun 30 2009

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Keywords

  • Costimulation
  • IL-17
  • Immunosuppression
  • Rejection

ASJC Scopus subject areas

  • General

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