Streptococcus pneumoniae is a leading cause of community-acquired pneumonia, yet the immune mechanisms required for protection against invasive pulmonary infection remain incompletely understood. Using a murine model of homologous protection against invasive pneumococcal pneumonia, we investigated the relative contribution of humoral and cellular immunity through adoptive serum transfer, immune cell depletion, and lung transcriptional profiling. Passive transfer of immune serum conferred robust protection, whereas neutrophil depletion impaired bacterial control, demonstrating that antibodies and neutrophils are key mediators of protection. In contrast, depletion of CD4+ T cells or NK cells did not compromise survival. Although IL-17A has been widely implicated in host defense against pneumococcal infection, IL-17A- deficient mice remained protected, albeit with delayed clearance and reduced early antibody responses. This delay was associated with compensatory upregulation of IL-17F and increased expression of Th1-associated genes in the lung. Together, these findings indicate that IL-17A is not essential for protection and support a model in which coordinated Th1 and Th17-related cytokine responses collectively promote neutrophil recruitment and effective antibody-mediated defense. These results highlight functional redundancy within the IL-17 cytokine axis and suggest that integrated cytokine networks, rather than individual mediators, underpin protective immunity to pneumococcal pneumonia, with implications for next-generation vaccine design.

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia, yet the immune mechanisms required for protection against invasive pulmonary infection remain inadequately understood. Using a murine model of homologous protection against invasive pneumococcal pneumonia, we explored the relative contributions of humoral and cellular immunity using adoptive serum transfer, immune cell depletion, and lung transcriptional profiling. Our findings indicated that passive transfer of immune serum provided robust protection, while neutrophil depletion significantly compromised bacterial control, highlighting that both antibodies and neutrophils are key mediators of protection. In contrast, depletion of CD4⁺ T cells or NK cells did not compromise survival. Although IL-17A has been widely implicated in host defense against pneumococcal infection, IL-17A-deficient mice remained protected, albeit with delayed clearance and reduced early antibody responses. We associate this delay with compensatory upregulation of IL-17F and increased expression of Th1-associated genes in the lungs. Together, these findings indicate that IL-17A is not essential for protection and support a model in which coordinated Th1- and Th17-related cytokine responses collectively promote neutrophil recruitment and effective antibody-mediated defense. These results highlight functional redundancy within the IL-17 cytokine axis and suggest that integrated cytokine networks, rather than individual mediators, underpin protective immunity to pneumococcal pneumonia, with implications for next-generation vaccine design.