Selective CD4 T cell help for B cell and antibody responses to vaccinia

Abstract

Selective CD4 T cell help for B cell and antibody responses to vacciniaIt remains unclear what parameters determine which pathogen proteins are targeted by the host antibody response. Peptide vaccination of mice with individual MHC II restricted vaccinia virus epitopes revealed that after vaccinia (smallpox vaccine) infection CD4 T cell help to B cells was surprisingly non‐transferable to B cells specific for different vaccinia virus proteins, including other virion surface or core proteins. This restriction had a direct impact on neutralizing antibody titers. Furthermore, large scale analysis of the antibody and CD4 T cell response specificities recognized during a vaccinia virus infection revealed that many of the CD4 T cell responses (identified in an unbiased screen) targeted viral virion proteins that were also targets of antibody responses, consistent with a deterministic linkage between the specificities (P < 0.0009). We then tested the deterministic linkage model by using this knowledge to efficiently predict new vaccinia virus MHC II epitopes (830% increase in identification efficacy). In contrast to the standard intermolcular help model, these data indicate that individual proteins are the primary unit of immunological recognition for a large virus, and therefore MHC II restriction at the protein level is a key selective event for the antiviral antibody response, which is likely of great relevance for vaccine development to large pathogens.