PI3Ks display integrant significance in T-cell development and differentiation, which is related to host defense against infections. Here, we investigated the role of p110δ isoform of PI3Ks in host defense against chlamydial lung infection in a mouse model. Our data showed that lung infection with Chlamydia muridarum (Cm) activated PI3K/AKT signaling pathway. Compared to WT mice, p110δD910A mice, mice with an inactivating knockin mutation in the p110δ Isoform of PI3Ks, showed more sever disease phenotype and slower recovery, which was associated with reduced Chlamydia-specific Th1 and Th17 immune responses following infection. Further adoptive transfer experiment showed that mice which received CD4+ T cells from infected p110δD910A mice exhibited greater body weight loss and higher bacterial loads in the lung than those which received CD4+ T cells from WT mice following challenge infection. These results provide in vivo evidence that p110δ isoform of PI3Ks plays an important role in host defense against chlamydial infection by promoting CD4+ T-cell immunity.