Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8+ T cell immunity during gammaherpesvirus infection

D. F. Pinelli, B. S. Wakeman, M. E. Wagener, S. H. Speck, M. L. Ford*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4-Ig fusion protein, patients showed an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8+ T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus-specific CD8+ T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4-Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen-specific CD8+ T cells. However, the addition of rapamycin to the CTLA4-Ig regimen was able to quantitatively and qualitatively restore the antigen-specific CD8+ T cell response to the virus. This improvement was physiologically relevant, in that CTLA4-Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus-specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients.

Original languageEnglish (US)
Pages (from-to)2576-2587
Number of pages12
JournalAmerican Journal of Transplantation
Volume15
Issue number10
DOIs
StatePublished - Oct 1 2015

Keywords

  • Immunosuppressant
  • infection and infectious agents
  • mechanistic target of rapamycin (mTOR)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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