Innate IFN-γ Is Essential for Systemic Chlamydia muridarum Control in Mice, While CD4 T Cell-Dependent IFN-γ Production Is Highly Redundant in the Female Reproductive Tract.

Abstract

Protective immunity against the obligate intracellular bacterium Chlamydia has long been thought to rely on CD4 T cell-dependent gamma interferon (IFN-γ) production. Nevertheless, whether IFN-γ is produced by other cellular sources during Chlamydia infection and how CD4 T cell-dependent and -independent IFN-γ contribute differently to host resistance have not been carefully evaluated. In this study, we dissected the requirements of IFN-γ 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-γ-deficient and T cell-deficient mice exhibited opposite phenotypes for survival and bacterial shedding at the FRT mucosa, demonstrating the distinct requirements for IFN-γ and CD4 T cells in host defense against Chlamydia In Rag1-deficient mice, IFN-γ 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-γ producers, we found that mature NK cells and ILC1s were not the sole sources of innate IFN-γ in response to Chlamydia By conducting T cell adoptive transfer, we showed definitively that IFN-γ-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-γ-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-γ is essential for preventing systemic Chlamydia dissemination, whereas IFN-γ produced by CD4 T cells is largely redundant at the FRT mucosa.