The role of regulatory T and B cells in host responses to Chlamydia genital tract infection

Abstract

The existence of regulatory T and B cells as important cellular entities in immune responses to infection has been established. The focus of this study was to dissect the role of regulatory T and B cells in regulating the pathogenesis of Chlamydia infection, a common cause of immunopathological disease sequelae. The functional role of CD4+Foxp3+CD25+ regulatory T cells (Tregs) in host responses to Chlamydia was investigated in an in vitro co-culturing system and a murine model of Chlamydia genital tract (GT) infection. Remarkably, Chlamydia infection subverted the immune suppressive role of CD4+Foxp3+ Tregs; instead of hampering immune responses, Tregs promoted pathological T helper (Th17) responses to Chlamydia in both in vitro and in vivo settings. Anti-CD25 monoclonal antibody treatment depleted Tregs prior to Chlamydia GT infection and markedly reduced the frequency and the total number of Th17 but not T helper 1 (Th1) cells at both immune induction and memory phases. Importantly, Treg-depleted mice displayed significantly attenuated neutrophilic inflammation and reduced severity of oviduct pathology. To our knowledge, this is the first demonstration that the level of endogenous host Tregs has a major impact on the development Chlamydia-associated diseases. In addition to Tregs, we investigated the role of B cells as a source of counter-regulatory IL-10, an immunosuppressive anti-Th1 cytokine, in host responses to Chlamydia. B cells were major IL-10 producers in response to Chlamydia in vitro. In particular, an IL-10+ CD43- B cell subset strongly suppressed CD4+ T cell proliferation and IFN- production in vitro. Notably, dendritic cells were required for the generation of CD43- IL-10+ B cells in response to Chlamydia in vitro. Importantly CD43-IL-10+ B cells were potently expanded in the local draining lymph node by day 5 following Chlamydia GT infection and selective deficiency of IL-10 in B cells markedly enhanced Th1 responses and decreased bacterial burden, reducing the severity of oviduct pathology. To our knowledge, this is the first report demonstrating a regulatory role for IL-10+ B cells in Chlamydia infection. Collectively, these results demonstrate that regulatory T and B cells have critical and distinct roles in modulating protective and pathological immune responses to Chlamydia.