Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

Hidetoshi Tsuda, Charles A. Su, Toshiaki Tanaka, Katayoun Ayasoufi, Booki Min, Anna Valujskikh, Robert L. Fairchild

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade-induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig-resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig-resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell-graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number4
DOIs
StatePublished - Feb 22 2018
Externally publishedYes

Keywords

  • Cellular immune response
  • Costimulation
  • Immunology
  • Transplantation

ASJC Scopus subject areas

  • Medicine(all)

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