Vγ1+ γδ T cell-derived IL-4 initiates CD8 T cell immunity

Abstract

Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full DC activation. Immunisation with sporozoites from Plasmodium leads to CD8 T cell priming in a complex response that is initiated by a collaboration between conventional type 1 DC (cDC1) and {gamma}{delta} T cells. We unveil a pivotal initiating role for V{gamma}1+ {gamma}{delta} T cells, as they directly supply IL-4 to DC and CD8 T cells. IL-4 synergises with a CD4 T cell-derived CD40L signal to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal CD8 T cells, with synergy between these cytokines driving enhanced IL-12 receptor expression and expansion of responding CD8 T cells. This study reveals a key role for V{gamma}l+ {gamma}{delta} T cells in initiating CD8 T cell immunity to Plasmodium. More broadly, it shows that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.