<p>IL-21/IL-21R signaling is crucial in various immune diseases and cellular development, however, its role in bacterial pneumonia remains unclear. Here, IL-21R knockout (IL-21R⁻^/−) mice were more susceptible to <i>Actinobacillus pleuropneumoniae</i> (APP) than wild-type (WT) mice. High-dimensional mass cytometry analysis revealed that IL-21R deficiency inhibited neutrophil activation, decreased the numbers of monocytes and proinflammatory macrophages, and augmented the defective CD3^low T cells in the lungs. Intracellular cytokine staining showed decreased IFN-γ/TNF-α/IL-6 production in IL-21R⁻^/− mice, particularly in CD8⁺ T cells. Furthermore, a previously unrecognized Ly6C⁺Ly6G⁺CD4⁺ T cell subset emerged only in the lungs of WT mice post-APP infection, which was in an activated status with stronger secretion capacities of IL-10, IL-21, granzyme B, and perforin by flow cytometry. These cells polarized macrophages into M2- or M1- phenotype without/with infection, respectively, and enhanced proliferation, phagocytosis, and macrophage extracellular traps/ROS-mediated bactericidal activity of macrophages against-APP, <i>Klebsiella pneumoniae</i>, or <i>Escherichia coli</i> infection. Thus, our study demonstrated that IL-21 drives the differentiation of neutrophils, monocytes, and macrophages into pro-inflammatory subsets. IL-21-induced Ly6C⁺Ly6G⁺CD4⁺ T cells cooperate with macrophages to enhance bacterial clearance, providing a promising target for preventing bacterial pneumonia.</p><p></p>