CD4 + cell depletion accelerates dendritic cell migration and enhances resident dendritic cell proliferation in tumor-draining lymph nodes.

Depletion of CD4+ cells during an anti-tumor immune response promotes tumor regression and accelerates proliferation of tumor-antigen-specific CD8+ T cells in draining lymph nodes (dLNs). However, the effect of the depletion on inter-organ kinetics of antigen presentation and qualitative changes in dendritic cells (DCs) are not yet understood. Here, we established a novel approach for simultaneous detection of cellular movement and cell cycle phase in vivo by KikGR/Fucci mice and used it to examine migratory and LN resident DC (LNDC) dynamics after CD4+ cell depletion. We found that CD4+ cell depletion enhanced migration of CD11c+ MHC class IIhigh migratory DCs from tumor to dLNs and induced activation-associated phenotypic changes, such as increased MHC class II expression. Despite reduced overall cellularity in tumor dLNs, LNDC numbers were relatively maintained. Within the LNDC compartment, CD4 depletion increased the relative abundance of a CD8α+CD11b+ subset and promoted influx and cell-cycle activity among newly recruited LNDCs. Publicly available single-cell RNA sequencing data further delineated ligand-receptor expression relationships, including Flt3l-Flt3 and Csf2-Csf2ra/Csf2rb axes, within tumor dLNs. These findings reveal remodeling of DC migration, activation, and LNDC turnover within tumor dLNs in the context of CD4+ cell depletion, which enhanced anti-tumor immunity.