A study on the role of Semaphorin 3E-PlexinD1 axis in dendritic cells for immunity to chlamydial infection

Abstract

Semaphorin 3E (Sema3E) has emerged as a novel mediator of immune responses. However, its function in immunity to bacterial infection has yet to be investigated. Using a mouse model of chlamydial lung infection, I demonstrated that Sema3E plays a significant role in the host immune response to the infection. Sema3E deficiency has a detrimental impact on disease course, dendritic cell (DC) function, and T cell responses. Sema3E knockout (KO) mice exhibited higher bacterial burden, severe body weight loss, and pathological changes after Chlamydia muridarum lung infection than wild-type (WT) mice. The severity of disease in Sema3E KO mice was correlated with reduced Th1/Th17 responses, increased Th2 response, altered Ab response, and higher Treg cells. Additionally, DCs isolated from Sema3E KO mice showed lower surface expression of co-stimulatory molecules and production of IL-12 but higher expression of PD-L1, PD-L2, and IL-10 production. Upon adoptive transfer, mice receiving DCs from Sema3E KO mice, unlike those receiving DCs from WT mice, were not protected against challenge infection. Moreover, Sema3E signaling on DC is crucial for their enhanced migration after chlamydial infection. C. muridarum infected Sema3E deficient DCs have impaired ability to respond to CCL19 in vitro and migrate to the lymph node in vivo. Further analysis of downstream signaling events showed that Sema3E deficiency reduces Rac1GTP, F-actin polymerization, Erk, and Akt phosphorylation in Cm infected DC upon CCL19 stimulation. Dendritic cells express the Sema3E high-affinity receptor, PlexinD1, which makes them responsive to Sema3E. CD11c PLXND1-/- mice (mouse deficient in PlexinD1 on dendritic cells) exhibited increased severity of Cm infection with lower IFN γ production and IL-17 cytokine production compared to CD11c PLXND1+/+ mice. I also found that PlexinD1 deficiency altered the phenotype and cytokine production pattern of DCs following Chlamydia muridarum infection. To investigate the translational significance of the findings, Chlamydia muridarum infected mice were treated with exogenous Sema3E. Sema3E treatment reduced chlamydial infection in the lung by promoting the Th1/Th17 response and inhibiting the Treg response. In conclusion, Sema3E acts as a critical factor for protective immunity against intracellular bacterial infection by modulating DC functions and T cell subsets.