Impact of selective CD28 blockade on virus-specific immunity to a murine Epstein-Barr virus homolog

• Type of Material: Article
• Authors: R. L. Crepeau, Emory University; J. A. Elengickal, Emory University; G. M. La Muraglia, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2019-08-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.15321
• Title of Journal or Parent Work: American Journal of Transplantation
• Volume: 19
• Issue: 8
• Start Page: 2199
• End Page: 2209
• Grant/Funding Information: This work was funded by NIH/ NIAID awards R01 AI104699, R01AI073707, and T32 AI070081.
• Keywords: Belatacept; Domain antibody antagonist; animal models; Costimulation; T-cells; differentiation; belatacept; Disease; murine; maturation; Science & Technology; lymphocyte biology; CTLA-4; Surgery; cellular biology; Responses; costimulation molecule specific; Safety; immunosuppressant-fusion proteins and monoclonal antibodies; basic (laboratory) research; T cell biology; science; Life Sciences & Biomedicine; Epstein-Barr Virus; Efficacy; Activation; Transplantation
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell; Biology, Virology

Abstract

CTLA-4Ig (belatacept) blocks the CD80/CD86 ligands for both CD28 and CTLA-4; thus, in addition to the intended effect of blocking CD28-mediated costimulation, belatacept also has the unintended effect of blocking CTLA-4–mediated coinhibition. Recently, anti-CD28 domain antibodies (dAb) that selectively target CD28 while leaving CTLA-4 intact were shown to more effectively inhibit alloimmune responses and prolong graft survival. However, the impact of selective CD28 blockade on protective immunity has not been extensively investigated. Here, we sought to compare the impact of CTLA-4Ig vs anti-CD28dAb on CD8+ T cell immunity to a transplant-relevant pathogen, a murine homolog of Epstein-Barr virus. Mice were infected with murine gammaherpesvirus-68 (MHV) and treated with vehicle, CTLA-4Ig, or anti-CD28dAb. Although anti-CD28dAb resulted in a decrease in virus-specific CD8+ T cell numbers as compared to CTLA-4Ig, cytolytic function and the expression of markers of high-quality effectors were not different from CTLA-4Ig treated animals. Importantly, MHV-68 viral load was not different between the treatment groups. These results suggest that preserved CTLA-4 coinhibition limits MHV-specific CD8+ T cell accumulation, but the population that remains retains cytolytic function and migratory capacity and is not inferior in its ability to control viral burden relative to T cell responses in CTLA-4Ig-treated animals.