Shirley Le, Nick Dooley, Declan G. Murphy, Shangyi Liu, Luke C. Gandolfo, Zhengyu Ge, Rose May, Anton Cozijnsen, Thomas N. Burn, Charlie Jennison, Annabell Bachem, Calvin Xu, Hui‐Fern Koay, Jan Schröder, Damian A. Oyong, Mayimuna Nalubega, Enny Kenangalem, Stéphanie Gras, Ian A. Cockburn, Sammy Bedoui, Laura K. Mackay, Geoffrey I. McFadden, Daniel Fernandez-Ruiz, Michelle J. Boyle, William R. Heath, Lynette Beattie
Abstract Dendritic cells (DCs) are pivotal for initiating adaptive immunity, a process triggered by the activation of DCs via pathogen products or damage. Immunization with sporozoites from Plasmodium leads to CD8 + T cell priming in a response initiated by collaboration between conventional type 1 DCs (cDC1s) and γδ T cells. Here we show that Vγ1 + γδ T cells have an initiating role by directly supplying interleukin-4 (IL-4). IL-4 and interferon-γ (IFNγ) synergize with CD4 + T cell-derived CD40L to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal responding CD8 + T cells and drive enhanced IL-12 receptor expression and expansion. This study shows how Vγ1 + γδ T cells can initiate CD8 + T cell immunity to Plasmodium and 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.