CD4+CD25+Foxp3+ Regulatory T Cells Promote Th17 Responses and Genital Tract Inflammation upon Intracellular Chlamydia muridarum Infection

Abstract

The functional role of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in host responses to intracellular bacterial infection was investigated in an in vitro coculturing system and a murine model of Chlamydia muridarum genital tract infection. Remarkably, C. muridarum infection subverted the immune suppressive role of CD4+CD25+Foxp3+ Tregs; instead of hampering immune responses, Tregs not only promoted Th17 differentiation from conventional CD4+ T cells but also themselves converted into proinflammatory Th17 cells in both in vitro and in vivo settings. Anti-CD25 mAb PC61 treatment to deplete ∼50% of pre-existing Tregs prior to C. muridarum genital tract infection markedly reduced the frequency and the total number of Th17 but not Th1 CD4+ cells at both immune induction and memory phases. Most importantly, Treg-depleted mice displayed significantly attenuated inflammation, neutrophil infiltration, and reduced severity of oviduct pathology upon C. muridarum genital infection. To our knowledge, this is the first report demonstrating that the level of pre-existing CD4+CD25+Foxp3+ Tregs in Chlamydia-infected hosts has a major impact on the development Chlamydia-associated diseases.

Th17 cells and Tregs: unlikely allies

“…Subsequently, Xu and colleagues [65] reported that in the presence of IL-6, T regs not only induced IL-17 expression by T effs but themselves also expressed IL-17. Coculturing of T effs with T regs inhibited production of the Th1 cytokine (IFN-␥) and Th2 cytokine (IL-4), whereas IL-17 family cytokines, including IL-17A, IL-17F, IL-21, and IL-22, were markedly enhanced [66,67]. This in vitro effect of T regs in promoting Th17 differentiation was reportedly mediated by providing TGF-␤ [65] and consumption of IL-2 [67].…”

“…Intriguingly, partial depletion of T regs markedly reduced the Th17 responses, as shown by the attenuated neutrophil infiltration and reduced severity of oviduct inflammation after C. muridarum genital infection [66]. Thus, T regs play a critical role in the immunopathogenesis in this model, which is completely contradictory to their well-documented immunosuppressive activity.…”

“…More recently, it has been shown that upon intracellular Chlamydia muridarum infection, T regs not only promoted Th17 differentiation from conventional CD4 ϩ T cells but also themselves converted into proinflammatory Th17 cells in in vitro and in vivo settings [66]. Intriguingly, partial depletion of T regs markedly reduced the Th17 responses, as shown by the attenuated neutrophil infiltration and reduced severity of oviduct inflammation after C. muridarum genital infection [66].…”

Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells

“…42 In addition, neutrophilassociated gene set signatures were also identified within the proteomic data set, although these do not preclude the involvement of other immune cell types. Neutrophils have been widely reported to accumulate in the FRT during infections, 43,44 but interestingly have also reported to have a critical role in endometrial degradation and repair during normal menstruation. 45,46 Preliminary data suggest that neutrophils are the most common cell recovered from endocervical cytobrush sampling.…”

IL-17 Deficiency Attenuates Allograft Injury and Prolongs Survival in a Murine Model of Fully MHC-Mismatched Renal Allograft Transplantation

“…In contrast, Tregs modulate these responses to induce donor-specific tolerance via both contact-dependent and independent mechanisms. Recently, there is a growing body of literature to suggest these two cell populations may act cooperatively in a variety of pathological processes (44)(45)(46).…”