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 language | English (US) |
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Pages (from-to) | 2576-2587 |
Number of pages | 12 |
Journal | American Journal of Transplantation |
Volume | 15 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2015 |
Keywords
- Immunosuppressant
- infection and infectious agents
- mechanistic target of rapamycin (mTOR)
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)