Impaired functions of human monocyte-derived dendritic cells and induction of regulatory T cells by pathogenic Leptospira.

Leptospirosis is a global zoonosis caused by pathogenic Leptospira. The disease outcome is influenced by the interplay between innate and adaptive immune responses. Dendritic cells (DCs) play a crucial role in shaping the adaptive immune response. A recent study revealed that pathogenic Leptospira limited the activation of human monocyte-derived dendritic cells (MoDCs) compared to non-pathogenic Leptospira, but their impact on T-cell responses has not been investigated. Our study is the first to explore how viable pathogenic and non-pathogenic Leptospira affect the interaction between human MoDCs and T cells. We found that MoDCs infected with pathogenic leptospires (L. interrogans serovar Pomona and a clinical isolate, MoDCs-P) exhibited lower levels of CD80 and CD83 expression, suggesting partially impaired MoDC maturation, induced regulatory T cells (Tregs) while failing to induce CD4⁺ T cell proliferation, compared to MoDCs infected with non-pathogenic leptospires (L. biflexa serovar Patoc and L. meyeri serovar Ranarum, MoDCs-NP). In contrast, non-pathogenic leptospires enhanced MoDC maturation and induced higher T cell proliferation including IFN-γ-producing CD4⁺ T cells, indicative of a Th1-type response. Furthermore, pathogenic leptospires induced higher MoDC apoptosis through a cysteine aspartic acid-specific protease-3 (caspase-3)-dependent pathway and upregulated expression of the prostaglandin-endoperoxide synthase 2 (PTGS2) gene. Notably, prostaglandin E2 (PGE2), a product of the PTGS2 pathway, was found at higher levels in the sera of patients with acute leptospirosis and in the supernatant of MoDCs-P, possibly contributing to Treg induction, compared to those of healthy donors and MoDCs-NP, respectively. In conclusion, this study reveals a novel immunosuppressive strategy employed by pathogenic Leptospira to evade host immunity by partially impairing MoDC maturation and inducing Tregs. These findings deepen our understanding of leptospirosis pathogenesis in humans and may provide a novel strategy to modulate DCs for the prevention and treatment of the disease. Author summary: Dendritic cells (DCs) are critical antigen-presenting cells that link between innate and adaptive immune responses against pathogens. However, their role in the pathogenesis of human leptospirosis remains unclear. This study provides the first evidence of the impact of leptospires on MoDC-CD4⁺ T cell responses. We observed that pathogenic leptospires partially impaired MoDC maturation, potentially compromising their ability to induce CD4⁺ T cell proliferation while inducing regulatory T cells (Tregs). Notably, pathogenic leptospires upregulated the PTGS2 gene expression, resulting in elevated prostaglandin E2 (PGE2) levels, which may contribute to Treg activation. Furthermore, pathogenic leptospires trigger more MoDC apoptosis, partly through a caspase-3-dependent pathway, compared to non-pathogenic strains. These findings might reveal the mechanisms that pathogenic leptospires used to evade the host immune response, facilitating their dissemination within the host. Conversely, non-pathogenic leptospires promote MoDC maturation and stimulate the proliferation of IFN-γ-producing CD4⁺ T cells, potentially eliciting a Th1-type response. In conclusion, our study reveals a novel strategy employed by pathogenic leptospires for immune evasion while highlighting the immune-activating effects of non-pathogenic strains. [ABSTRACT FROM AUTHOR]