Rapamycin ameliorates the CTLA4‐Ig–mediated defect in CD8+ T cell immunity during gammaherpesvirus infection. Issue 10 (19th May 2015)

• Record Type: Journal Article
• Authors: Pinelli, D. F.; Wakeman, B. S.; Wagener, M. E.; Speck, S. H.; Ford, M. L.
• Is Part Of: American journal of transplantation. Volume 15:Issue 10(2015:Oct.)
• Page Start: 2576
• Page End: 2587
• Publication Date: 2015-05-19
• Subjects: Immunosuppressant -- infection and infectious agents -- mechanistic target of rapamycin (mTOR); Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.13326
• Languages: English
• ISSNs: 1600-6135

Abstract

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. Abstract : Using a murine model of gammaherpesvirus infection, this study demonstrates that treatment with rapamycin augments the anti‐viral CD8+ T cell response in the presence of CTLA4‐Ig and leads to an improved ability to control viral burden in infected animals.