The Number of Respiratory Syncytial Virus (RSV)-Specific Memory CD8 T Cells in the Lung Is Critical for Their Ability to Inhibit RSV Vaccine-Enhanced Pulmonary Eosinophilia

Abstract

Children that were administered a formalin-inactivated respiratory syncytial virus (FI-RSV) vaccine experienced enhanced respiratory disease, including pulmonary eosinophilia, after contracting a natural RSV infection. RSV vaccine-enhanced disease can be mimicked in BALB/c mice immunized with either FI-RSV or with a recombinant vaccinia virus (vacv) expressing the RSV attachment (G) protein. We have recently demonstrated that memory CD8 T cells directed against the RSV immunodominant M282–90 epitope inhibit the development of pulmonary eosinophilia in either vacvG- or FI-RSV-immunized mice by reducing the total number of Th2 cells in the lung after RSV challenge. In this study, we show that memory CD8 T cells specific to a subdominant epitope within the RSV fusion (F) protein fail to inhibit the development of pulmonary eosinophilia after RSV challenge of mice previously co-immunized with vacvF and with either vacvG or FI-RSV. We observed that the inability of RSV F85-specific memory CD8 T cells to inhibit the development of pulmonary eosinophilia was largely due to an inadequate total number of F85-specific memory CD8 T cells in the lung at early times after RSV challenge. Increasing the number of F85-specific memory CD8 T cells after immunization grants these cells the ability to inhibit RSV vaccine-enhanced pulmonary eosinophilia. Moreover, we demonstrate that RSV-specific memory CD8 T cells, when present in sufficient numbers, inhibit the production of the Th2-associated chemokines CCL17 and CCL22. Taken together, these results indicate that RSV-specific memory CD8 T cells may alter the trafficking of Th2 cells and eosinophils into the lung.

Efficient Lung Recruitment of Respiratory Syncytial Virus-Specific Th1 Cells Induced by Recombinant Bacillus Calmette-Guérin Promotes Virus Clearance and Protects from Infection

“…This was probably due to a deficient TLR activation in B cells (12). The pathological manifestations caused by RSV in mice that were previously vaccinated with FI-RSV were characterized by pulmonary eosinophilia and mixed Th1/Th2 CD4 + T cell responses (13)(14)(15). Similar observations were made in mice immunized with recombinant vaccinia virus expressing the RSV-G protein (16).…”

“…However, this response by itself is not capable of reverting RSV infection and disease. Probably, IFN-g secreted in response to BCG WT alone led to the attenuation of the strong and damaging Th2 reactions that are generally associated with the subsequent intranasal RSV challenge, as is the case with our UV-RSV control (3) or FI-RSV and recombinant vaccinia virus expressing the RSV-G protein in other reports (15,53). A prominent hypothesis to explain these results is that the prior immune history of a host can change the cytokine milieu of a particular tissue or organ (in this case the lung).…”

“…Several studies have shown that RSV can modulate host immunity by blocking the activation, expansion, and function of cytotoxic and memory T cells (14,15,22,43,44). As a result, primary infection does not confer immune protection against subsequent reinfections with antigenically similar RSV strains (45,46).…”

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

“…How the Th1 and Th2 arms of the virus-specific immune response reciprocally interact in these models is unclear. Suppression of Th2-induced disease in the FI-RSV model can be accomplished when CD8 ϩ T cell responses are boosted early during challenge, i.e., in mice preimmunized with the dominant CD8 ϩ T cell epitope (34,35). However, the virusspecific CD8 ϩ T cell response and CD4 ϩ T cell-mediated IFN-␥ responses were not different early after viral challenge in mice receiving the scGOS/lcFOS/pAOS diet.…”

Determining the Breadth of the Respiratory Syncytial Virus-Specific T Cell Response

“…Mice were immunized with 3 ϫ 10 6 PFU VacV-F by scarification at the base of the tail (26). Twenty-one days following immunization, mice were infected with RSV.…”