Pathogen stimulation history impacts donor-specific CD8+ T cell susceptibility to costimulation/integrin blockade-based therapy

I. R. Badell, W. H. Kitchens, M. E. Wagener, A. E. Lukacher, C. P. Larsen, M. L. Ford

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8+ memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation. Donor-specific T cell memory elicited by three distinct infections influences murine skin allograft survival in response to costimulation blockade-based immunosuppression in a pathogen-dependent manner.

Original languageEnglish (US)
Pages (from-to)3081-3094
Number of pages14
JournalAmerican Journal of Transplantation
Volume15
Issue number12
DOIs
StatePublished - Dec 2015

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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