Porcine contagious pleuropneumonia caused by Actinobacillus pleuropneumoniae (APP) is a fatal respiratory disease that threatens the worldwide farming industry’s health. The immune responses of extrapulmonary tissues play an important role in developing porcine contagious pleuropneumonia; however, the immune responses of extrapulmonary tissues induced by APP are rarely uncovered. Here, we used high-dimensional mass cytometry to investigate the immune cell response in the spleen and peripheral blood during APP infection in mice. We found that the immune response triggered by APP was highly tissue-specific. Numerous infection time- or tissue-specific immune cell clusters, including previously unrecognized ones, were also identified in the spleen and peripheral blood. Integrative analysis of splenic lymphoid and myeloid cell clusters maps the dynamic immune response cellular network during APP infection. Surprisingly, during the early stages of APP infection, the majority of the top 6 cell clusters contributing to the infection time-specificity in the spleen were adaptive immune cell clusters rather than innate immune cell clusters, among which CD24hiMHCII+CD8+TEM cells exhibited a stronger expression of IFN-γ, IL-17A, and IL-10 compared to the CD24lo compartment. In peripheral blood, there was unprecedented heterogeneity in the immune cell composition. Also, peripheral immune cell clusters closely related to the severity of APP infection were identified. In summary, our data provide a systemic and comprehensive overview of the immune responses to APP infection in the spleen and peripheral blood. This provides a foundation for understanding the immune pathogenesis of APP and identifying potential diagnostic biomarkers and therapeutic targets.