Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice.

Protective immune responses to Chlamydia infection within the female reproductive tract (FRT) are incompletely understood. MHC class II-restricted CD4 Th1 responses are believed to be vital for bacterial clearance due to their capacity to secrete IFN-γ, but an essential requirement for T-bet-expressing Th1 cells has yet to be demonstrated in the mouse model of Chlamydia infection. Here, we investigated the role of T-bet and IFN-γ in primary clearance of Chlamydia after FRT infection. Surprisingly, IFN-γ producing CD4 T cells from the FRT expressed low levels of T-bet throughout infection, suggesting that classical T-bet-expressing Th1 cells are inefficiently generated and therefore unlikely to participate in bacteria clearance. Furthermore, mice deficient in T-bet expression or with a CD4-specific T-bet deficiency cleared FRT infection similarly to wild-type controls. T-bet-deficient mice displayed significant skewing of FRT CD4 T cells towards Th17 responses, demonstrating that compensatory effector pathways are generated in the absence of Th1 cells. In marked contrast, IFN-γ-, and IFN-γR-deficient mice were able to reduce FRT bacterial burdens, but suffered systemic bacterial dissemination and 100% mortality. Together, these data demonstrate that IFN-γ signaling is essential to protect mice from fatal systemic disease, but that classical T-bet-expressing Th1 cells are non-essential for primary clearance within the FRT. Exploring the protective contribution of Th1 cells versus other CD4 effector lineages could provide important information for the generation of new Chlamydia vaccines. Author summary: The production of IFN-γ by CD4 Th1 cells is thought to be critical for the clearance of Chlamydia from the female reproductive tract (FRT), but this has not been formally tested. Here we demonstrate that T-bet+ Th1 cells are not essential for effective Chlamydia clearance. Furthermore, the impact of IFN-γ deficiency or depletion is largely observed as a failure to control bacterial dissemination, rather than clearance from the FRT. Together, these data suggest that different immunological mechanisms are responsible for restraining systemic spread of bacteria versus FRT control. Defining alternative non-Th1 CD4 effector mechanisms that are responsible for controlling Chlamydia replication within the FRT could be foundational for future vaccine development. [ABSTRACT FROM AUTHOR]