Helminth-induced IL-4 expands bystander memory CD8⁺ T cells for early control of viral infection.

Abstract

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8⁺ T cells (T_VM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the T_VM compartment. Here, we show that helminths expand CD44^hiCD62L^hiCXCR3^hiCD49d^lo T_VM cells through direct IL-4 signaling in CD8⁺ T cells. Importantly, helminth-mediated conditioning of T_VM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8⁺ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8⁺ T cells, leading to a subsequently raised antigen-specific CD8⁺ T cell activation that enhances control of viral infection.