Innate Ifn-Gamma Is Essential For Systemic Chlamydia Muridarum Control In Mice, While Cd4 T Cell-Dependent Ifn-Gamma Production Is Highly Redundant In The Female Reproductive Tract

Protective immunity against the obligate intracellular bacterium Chlamydia has long been thought to rely on CD4 T cell-dependent gamma interferon (IFN-gamma) production. Nevertheless, whether IFN-gamma is produced by other cellular sources during Chlamydia infection and how CD4 T cell-dependent and -independent IFN-gamma contribute differently to host resistance have not been carefully evaluated. In this study, we dissected the requirements of IFN-gamma produced by innate immune cells and CD4 T cells for resolution of Chlamydia muridarum female reproductive tract (FRT) infection. After C. muridarum intravaginal infection, IFN-gamma-deficient and T cell-deficient mice exhibited opposite phenotypes for survival and bacterial shedding at the FRT mucosa, demonstrating the distinct requirements for IFN-gamma and CD4 T cells in host defense against Chlamydia. In Rag1-deficient mice, IFN-gamma produced by innate lymphocytes (ILCs) accounted for early bacterial control and prolonged survival in the absence of adaptive immunity. Although type I ILCs are potent IFN-gamma producers, we found that mature NK cells and ILC1s were not the sole sources of innate IFN-gamma in response to Chlamydia. By conducting T cell adoptive transfer, we showed definitively that IFN-gamma-deficient CD4 T cells were sufficient for effective bacterial killing in the FRT during the first 21 days of infection and reduced bacterial burden more than 1,000-fold, although mice receiving IFN-gamma-deficient CD4 T cells failed to completely eradicate the bacteria from the FRT like their counterparts receiving wild-type (WT) CD4 T cells. Together, our results revealed that innate IFN-gamma is essential for preventing systemic Chlamydia dissemination, whereas IFN-gamma produced by CD4 T cells is largely redundant at the FRT mucosa.