Endothelial semaphorin 6D controls immune responses under cold stress through regulation of sympathetic innervation.

Environmental temperature significantly influences immune responses. Cold exposure suppresses host defense against infections and exacerbates autoimmune and allergic conditions. However, the molecular mechanisms underlying temperature-dependent immune regulation remain unclear. In this study, we evaluated the cold-activated sympathetic modulation of immune responses. We presented that semaphorin 6D (Sema6D), an axon guidance molecule, is required for proper sympathetic nerve distribution. While both wild-type and Sema6d-/- mice developed experimental autoimmune encephalomyelitis (EAE) similarly at room temperature (22 °C), disease progression was attenuated in Sema6d-/- mice specifically under cold exposure (10 °C). Additionally, endothelial cell-specific Sema6d-/- (Sema6dΔVEcad) mice exhibited cold-specific attenuation of EAE development. Notably, Sema6dΔVEcad mice showed increased perivascular sympathetic innervation in lymph nodes, which resulted in enhanced norepinephrine-induced tissue hypoxia and cellular stress responses, leading to attenuated T-cell responses under cold exposure. These immunosuppressive effects were restored by pharmacological ablation of the sympathetic nerves, showing that the proper sympathetic nerve distribution in lymphoid organs is critical for immune competence under cold exposure. Collectively, these findings not only indicate that Sema6D is a key axon guidance molecule for sympathetic nerve distribution but also show a potential mechanism underlying the environmentally modulated progression of autoimmune diseases.