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

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(hi)CD62L(hi)CXCR3(hi)CD49d(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.