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

• Published in: American journal of transplantation Vol. 15; no. 10; pp. 2576 - 2587
• Main Authors: Pinelli, D. F., Wakeman, B. S., Wagener, M. E., Speck, S. H., Ford, M. L.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2015
• Subjects: Abatacept - adverse effects; Animal models; Animals; Antigens; CD28 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Clinical trials; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytokines; Drug Therapy, Combination; Epstein-Barr virus; Fusion protein; Gammaherpesvirinae; Herpesviridae Infections - drug therapy; Herpesviridae Infections - immunology; Immunity; Immunoglobulins; Immunosuppressant; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; infection and infectious agents; Infections; Lymphocytes; Lymphocytes T; mechanistic target of rapamycin (mTOR); Mice; Patients; Rapamycin; Sirolimus - pharmacology; Sirolimus - therapeutic use; T cell receptors; TOR protein; Viral infections; Immunosuppressant; infection and infectious agents; mechanistic target of rapamycin (mTOR)
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.13326

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. 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.