Semaphorin 3E Promotes Susceptibility to Leishmania major Infection in Mice by Suppressing CD4+ Th1 Cell Response

Abstract

Protective immunity to cutaneous leishmaniasis is mediated by IFN-g-secreting CD4 + Th1 cells. IFN-g binds to its receptor on Leishmania-infected macrophages, resulting in their activation, production of NO, and subsequent destruction of parasites. This study investigated the role of Semaphorin 3E (Sema3E) in host immunity to Leishmania major infection in mice. We observed a significant increase in Sema3E expression at the infection site at different timepoints following L. major infection. Sema3E-deficient (Sema3E knockout [KO]) mice were highly resistant to L. major infection, as evidenced by significantly (p < 0.05-0.01) reduced lesion sizes and lower parasite burdens at different times postinfection when compared with their infected wild-type counterpart mice. The enhanced resistance of Sema3E KO mice was associated with significantly (p < 0.05) increased IFN-g production by CD4 + T cells. CD11c + cells from Sema3E KO mice displayed increased expression of costimulatory molecules and IL-12p40 production following L. major infection and were more efficient at inducing the differentiation of Leishmania-specific CD4 + T cells to Th1 cells than their wild-type counterpart cells. Furthermore, purified CD4 + T cells from Sema3E KO mice showed increased propensity to differentiate into Th1 cells in vitro, and this was significantly inhibited by the addition of recombinant Sema3E in vitro. These findings collectively show that Sema3E is a negative regulator of protective CD4 + Th1 immunity in mice infected with L. major and suggest that its neutralization may be a potential therapeutic option for treating individuals suffering from cutaneous leishmaniasis.

Semaphorins in immune cell function, inflammatory and infectious diseases

“…1 ). On the other hand, Sema3E deficient Leishmania major infected mice exhibited enhanced resistance to infection compared to WT mice ( Ikeogu et al, 2021 ). Sema3E promotes susceptibility to Leishmania infection in mice by supressing Th1 immune response ( Ikeogu et al, 2021 ).…”

“…On the other hand, Sema3E deficient Leishmania major infected mice exhibited enhanced resistance to infection compared to WT mice ( Ikeogu et al, 2021 ). Sema3E promotes susceptibility to Leishmania infection in mice by supressing Th1 immune response ( Ikeogu et al, 2021 ). Enhanced resistance to L.major in Sema3E deficient mice was also associated with increased co-stimulatory molecules and 1L-12 cytokine production by CD11c + cells ( Ikeogu et al, 2021 ).…”

“…Sema3E promotes susceptibility to Leishmania infection in mice by supressing Th1 immune response ( Ikeogu et al, 2021 ). Enhanced resistance to L.major in Sema3E deficient mice was also associated with increased co-stimulatory molecules and 1L-12 cytokine production by CD11c + cells ( Ikeogu et al, 2021 ). The reason for the discrepancy between the role of Sema3E in Chlamydia and Leishmania infection remains unclear.…”

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…Th1 primarily secretes interleukin‐2 (IL‐2), IL‐12, interferon‐γ (IFN‐γ), and tumor necrosis factor‐α (TNF‐α), which facilitates Th1 proliferation and regulates cellular immunity. In addition, these cytokines inhibit Th2 proliferation 29,30 . IFN‐γ not only activates and enhances the phagocytic properties of macrophages but also promotes the production of immunoglobulin G 31,32 .…”

“…In addition, these cytokines inhibit Th2 proliferation. 29,30 IFN-γ not only activates and enhances the phagocytic properties of macrophages but also promotes the production of immunoglobulin G. 31,32 IL-2, IL-12, and IFN-γ can also enhance the killing ability of NK cells. 33 The proliferation and differentiation of cytotoxic T cells (CTLs) can be synergistically stimulated by IL-2 and IFNγ.…”