CD4+ T-cell help delivery to monocyte-derived dendritic cells promotes effector differentiation of helper and cytotoxic T cells

Abstract

Delivery of CD4⁺ T-cell help optimizes CD8⁺ T-cell effector and memory responses via CD40-mediated licensing of conventional dendritic cells (DCs). Using comparative vaccination settings that prime CD8⁺ T cells in presence or absence of CD4⁺ T-cell help, we observed that CD4⁺ T-cell activation promoted influx of monocytes into the vaccine-draining lymph nodes (dLNs), where they differentiated into monocyte-derived (Mo)DCs, as defined by the most recent standards. Abrogation of these responses by CCR2-targeted depletion indicated that monocyte-derived cells in the dLN promoted T-helper 1 (Th1) type effector differentiation of CD4⁺ T cells, as well as effector differentiation of CD8⁺ T cells. Monocyte-derived cells in dLNs upregulated CD40, CD80 and PD-L1 as a result of CD4⁺ T-cell help. The response of monocyte-derived cells to CD4⁺ T-cell help was independent of natural killer (NK) cells and proceeded via CD40 ligand (L)-CD40 interactions and IFNγ signaling. Our data argue for a scenario wherein activated CD4⁺ T cells in dLNs crosstalk via CD40L and IFNγ signals to monocytes, promoting their local differentiation into MoDCs. This event enhances formation of CD4⁺ Th1 and CD8⁺ cytotoxic effector T cell pool, most likely by virtue of their improved costimulatory status and cytokine production.