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 polyfu... More
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.
