Mucosal vaccine adjuvant cyclic di-GMP differentiates lung moDCs into Bcl6+ and Bcl6- mature moDCs to induce lung memory CD4+ TH cells and lung TFH cells respectively

Abstract

Induction of lung T-cell responses, including memory CD4+ TH and TFH cells, are highly desirable for vaccines against respiratory infections. We recently showed that the non-migratory monocytes-derived DCs (moDCs) induced lung TFH cells. However, the DCs subset inducing lung CD4+ memory TH cells is unknown. Here, using conditional knockout mice and adoptive cell transfer, we first established that moDCs are essential for lung mucosal, but are dispensable for systemic, vaccine responses. Next, we showed that intranasal administration of adjuvant cyclic di-GMP differentiated lung moDCs into Bcl6+ and Bcl6- moDCs promoting lung memory TH cells and lung TFH cells, respectively. Mechanistically, soluble TNF from lung TNFR2+ cDC2 subpopulation mediates the induction of lung Bcl6+ moDCs. Last, we designed fusion proteins targeting soluble or transmembrane TNF to lung moDCs and generated Bcl6+, Bcl6- lung moDCs respectively. Together, our study revealed lung mature moDCs heterogeneity and showed a moDCs-targeting strategy to enhance lung mucosal vaccine responses.