CD4+ T cells clear virus but augment disease in mice infected with respiratory syncytial virus. Comparison with the effects of CD8+ T cells

Abstract

SUMMARYRespiratory syncytial (RS) virus-specific T cell lines were derived from ihe spleens of BALB/c mice primed by intranasal infeclion with RS virus. The lines were expanded by repealed aniigenic stimulation in vitro, and separated into CD4' and CD8 ' T cell-enriched t raciions by immunomagnetie adhesion. The effects of passive Iransfer of these fractions into RS virus infected mice were observed. The most severe immiinopathological changes were seen in mice receiving CD4' cells. Transfer of CD4\ CDS • or both eell fractions caused RS virus-infecied mice to become ill and lose weight. Both eell lines eaused an increase in the severity of lung pathology (as monitored by bronchoalveolar lavage) with the appearance or lung haemorrhage and polymorphonuclear cell efflux. In addition, recipients of CD4' cells developed striking pulmonary eosinophilia. In CD4 ' cell recipients. 5x 10' eells were sufficient to decrease lung virus tilre. whereas 2x10'' CDS* cells were needed to produce a similar etfect. The unseparated T cell line and the CD4' cell fraction secreted significantamounlsofIL-3, IL-4 and IL-5 (/*< 0-001). High levels of IL-2 were produced only hy the unseparatedTcell line. The CDS " cell fraction secreted lL-3 only. The results show that, cell-for-cell. CD4' ceils are more anti-viral and more immunopalhogenic than CD8' cells in RS virus infected mice. Such effects may have contributed to the augmented disease seen in some infants vaccinated againsl RS virus. immune responses to RS virus infection. Mice infected wilh RS virus develop a lymphocytic infiltrate in the pulmonary epiihelium. dominated by CDS' T eells at the lime of virus elimination. This occurs before any serological response is detectable, and local epithelial B cells are remarkable by Iheir absence [ 12]. Polyelonal memory T eells can clear persistent RS virus infeetion in immunodefieient miee in the absence of RS virus-specific antibodies (13). as can transfer of CDS' CTL lines or clones-while also eausing haemorrhagic, neuirophilic and sometimes fata! pneumonitis [14]. The role of T helper cells in RS virus-induced imniunopaihology has not been fully examined. Openshaw ei al. [15] found that splenocytes from mice primed inlranasally wilh RS virus exhibited helper T cell memory (demonstrable by virus-specific lL-2 release) whereas those from unprimed mice did not.In order to develop safe and effective vaccines for RS virus, more needs lo be known about the T cell subpopulations involved in protective and harmful responses. Here we describe the in viiro selection, characterization and in rivo effects of cell linesenriched forCD4' andCD8' RS virus-specific Tcells. The CD4+ cells (and to a lesser extent the CDS * cells) redueed lung virus titre and augmented disease in syngcneic mice. 527

CD8 T Cells Inhibit Respiratory Syncytial Virus (RSV) Vaccine-Enhanced Disease

“…Previous work by several laboratories has shown that increased eosinophilia in vvG-and FI-RSV-immunized mice often correlates with enhanced systemic disease as measured by weight loss and illness scores (35)(36)(37)(38). Our data indicate that M2-specific CD8 T cells inhibit RSV vaccine-enhanced pulmonary eosinophilia; however it was unknown whether this reduction of pulmonary eosinophilia would correlate with reduced systemic illness.…”

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

“…It may be that other killing mechanisms or cell types are involved (47), for example, Treg cells, which use granzyme B to resolve inflammation after RSV infection (48), or CD8 cells, which have been shown to kill lymphocytic choriomeningitis virus-infected B cells (49). CD8 T cells have been shown to downregulate the Th2 CD4 T-cell response to RSV (50), and transferring RSV-specific CD8 cells into adult mice has an inhibitory effect on antibody responses (51). However, this does not explain why CD4 and CD8 codepletion enhanced antibody responses.…”

Influence of a Single Viral Epitope on T Cell Response and Disease After Infection of Mice with Respiratory Syncytial Virus

“…7 and our own unpublished observations), and the transfusion of virus-specific T cells into RSV-infected mice aggravates disease (8). Both CD4 ϩ and CD8 ϩ T cells can eliminate virus and cause immunopathology independently (9), but CD8…”