CD8+ Cells Enhance Resistance to Pulmonary Serotype 3 Streptococcus pneumoniae Infection in Mice

Abstract

Despite the success of the pneumococcal conjugate vaccine, pneumococcal pneumonia remains a significant clinical problem, and there is still much to learn about natural resistance and cellular immunity to pneumococcus. We investigated the role of T lymphocytes in resistance to serotype (ST) 3 Streptococcus pneumoniae in an intranasal infection model in C57BL/6 (wild-type [Wt]) and CD8+ (CD8−/−)- and CD4+ (MHC class II−/−)-deficient mice. CD8−/− mice exhibited significantly more bacterial dissemination and lung inflammation and a significantly more lethal phenotype than Wt mice. However, there was no difference in the bacterial dissemination, lung inflammation, or survival of Wt and MHC class II−/− mice. Perforin (Pfn)−/− and IFN-γ−/− mice, which were used to dissect the role of CD8+ T cells in our model, also exhibited a more lethal survival phenotype than Wt mice. Comparison of lung chemokine/cytokine levels by Luminex and cellular recruitment by FACS in Wt mice and knockout strains revealed that CD8−/− and IFN-γ−/− mice, which had the most lethal survival phenotype, had more CD4+IL-17+ T (Th17) cells, IL-17, neutrophil chemoattractants, and lung neutrophils, and fewer regulatory T cells than Wt mice. CD4+ T cell depletion improved the survival of ST-infected CD8−/− mice, and survival studies in Th17-deficient mice revealed that the Th17 response was dispensable for ST3 resistance in our model. Taken together, these findings demonstrate that CD8+ cells are required, but CD4+ T cells are dispensable for resistance to ST3 pneumonia in mice and suggest a previously unsuspected role for CD8+ cells in modulating the inflammatory response to ST3.

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

“…Furthermore, in the absence of IFN-g, decreased levels of chemokines involved in neutrophil recruitment, as well as neutrophils themselves, were reported by some groups (23,26), and this was associated with a lower bacterial load (23). More recently, and in contrast, IFN-g-deficient mice were argued to have higher levels of neutrophils and chemokines associated with their recruitment, as well as increased bacterial load (25). Alternatively, IFN-g may influence pneumococcal clearance via modulation of macrophage scavenger receptors.…”

“…More recently, it was shown that S. pneumoniae may also be recognized by inflammasomes that are dependent upon the adaptor molecule ASC (16)(17)(18)(19). Together, these pathways initiate immune activation and lead to production of inflammatory cytokines and chemokines that subsequently mediate the recruitment of leukocytes to the site of infection (20)(21)(22)(23)(24)(25)(26). However, when this occurs within the brain, the ensuing inflammatory response is argued to ultimately cause neuronal damage and/ or death (9,10).…”

“…In patients with S. pneumoniae sepsis, plasma IFN-g levels were reported to be elevated, and circulating levels of the cytokine correlated with mortality (44). In murine models, IFN-g inhibition/ ablation was reported to lead to decreased survival (25,26,45) or to have no effect on mortality (23,46). Furthermore, in the absence of IFN-g, decreased levels of chemokines involved in neutrophil recruitment, as well as neutrophils themselves, were reported by some groups (23,26), and this was associated with a lower bacterial load (23).…”

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

“…+ T cell responses play important roles in clearance of S. pneumoniae, contributing to the anti-microbial host response through activation of phagocyte-driven microbial killing, while CD8 + T cells may have important roles regulating the extent of Th17 responses and neutrophilic inflammation [40][41][42][43]. Although adaptive immune responses contribute to these responses, innate immunity can amplify responses in the form of monocyteinduced stimulation of memory T cells, and innate responses generated by cells such as invariant natural killer T cells (iNKT) can prime phagocyte bacterial killing [41,[43][44][45].…”

Interleukin‐10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae

“…The capacity of IL-10 to modulate the host inflammatory immune response together with the fact that lung inflammation during S. pneumoniae infection is associated with increased bacterial dissemination and severe disease, [23][24][25] would suggest that IL-10 is required to prevent bacterial dissemination during S. pneumoniae infection. Here we show that S. pneumoniae (strain D39) leads to a significant increase in the expression of IL-10 in the lungs of infected mice.…”