title: Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8(+) T cell immunity during gammaherpesvirus infection.
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.
authors.affiliation: Emory Transplant Center and Department of Surgery, Atlanta, GA.
authors.forename: D F
authors.initials: DF
authors.lastname: Pinelli
authors.affiliation: Emory Vaccine Center, Atlanta, GA.
authors.forename: B S
authors.initials: BS
authors.lastname: Wakeman
authors.affiliation: Emory Transplant Center and Department of Surgery, Atlanta, GA.
authors.forename: M E
authors.initials: ME
authors.lastname: Wagener
authors.affiliation: Emory Vaccine Center, Atlanta, GA.
authors.forename: S H
authors.initials: SH
authors.lastname: Speck
authors.affiliation: Emory Transplant Center and Department of Surgery, Atlanta, GA.
authors.forename: M L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000069594:Abatacept / Q000009:adverse effects*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D004359:Drug Therapy, Combination; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D060908:CTLA-4 Antigen; D007166:Immunosuppressive Agents; D000069594:Abatacept; D020123:Sirolimus
keywords: Immunosuppressant; infection and infectious agents; mechanistic target of rapamycin (mTOR)