Serum Antibodies Critically Affect Virus-Specific CD4+/CD8+ T Cell Balance during Respiratory Syncytial Virus Infections

Abstract

Following infection with respiratory syncytial virus (RSV), reinfection in healthy individuals is common and presumably due to ineffective memory T cell responses. In peripheral blood of healthy adults, a higher CD4+/CD8+ memory T cell ratio was observed compared with the ratio of virus-specific effector CD4+/CD8+ T cells that we had found in earlier work during primary RSV infections. In mice, we show that an enhanced ratio of RSV-specific neutralizing to nonneutralizing Abs profoundly enhanced the CD4+ T cell response during RSV infection. Moreover, FcγRs and complement factor C1q contributed to this Ab-mediated enhancement. Therefore, the increase in CD4+ memory T cell response likely occurs through enhanced endosomal Ag processing dependent on FcγRs. The resulting shift in memory T cell response was likely amplified by suppressed T cell proliferation caused by RSV infection of APCs, a route important for Ag presentation via MHC class I molecules leading to CD8+ T cell activation. Decreasing memory CD8+ T cell numbers could explain the inadequate immunity during repeated RSV infections. Understanding this interplay of Ab-mediated CD4+ memory T cell response enhancement and infection mediated CD8+ memory T cell suppression is likely critical for development of effective RSV vaccines.

Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

“…For preparation of lung tissue homogenates, isolated snap-frozen whole lungs were crushed on dry ice, dissolved in PBS, and stored at Ϫ80°C until further use. Viral replication in lung homogenates was determined, as earlier described, via plaque assay (24). To measure total virus copy numbers by PCR, total RNA from lung homogenates was extracted using MagnaPure LC equipment, cDNA was synthesized, and viral loads were determined by real-time PCR as recently described (19).…”

Intranasal Administration of Antibody-Bound Respiratory Syncytial Virus Particles Efficiently Primes Virus-Specific Immune Responses in Mice

“…Previously, we showed that the neutralizing capacity of RSV-specific antibodies influenced the level of virus-specific CD8 ϩ and CD4 ϩ T-cell responses in immune mice (14). Highly neutralizing serum antibodies decreased the CD8 ϩ T-cell response, while both neutralizing and nonneutralizing antibodies increased CD4 ϩ T-cell responses.…”

“…The 50% tissue culture infective dose (TCID 50 ) was determined after titration in HEp-2 cells. Detailed methods have been described previously (14).…”

“…Highly neutralizing serum antibodies decreased the CD8 ϩ T-cell response, while both neutralizing and nonneutralizing antibodies increased CD4 ϩ T-cell responses. The increased T-cell responses in the presence of antibodies was mediated by increased antigen presentation of RSV immune complexes (IC-RSV) to CD4 ϩ T cells in an Fc␥R-dependent process (14).…”

The Comparative Genomics of Human Respiratory Syncytial Virus Subgroups A and B: Genetic Variability and Molecular Evolutionary Dynamics

“…Early vaccination attempts in children in the 1960s with a formalin-inactivated RSV vaccine resulted in enhanced disease severity upon subsequent virus exposure (34)(35)(36)(37). It is thought that inadequate serum neutralizing-antibody levels, low CD8 ϩ memory T cell response, and enhanced CD4 ϩ memory T cell response were the consequences of this intensified disease profile (35,(38)(39)(40)(41). Later vaccination attempts with live, attenuated RSV vaccines did not show similar respiratory disease exacerbation upon natural infection but nevertheless failed to provide appreciable protection from infection.…”