Dendritic Cells Display Subset and Tissue-Specific Maturation Dynamics over Human Life

Maturation and migration to lymph nodes (LNs) constitutes a central paradigm in conventional dendritic cell (cDC) biology but remains poorly defined in humans. Using our organ donor tissue resource, we analyzed cDC subset distribution, maturation, and migration in mucosal tissues (lungs, intestines), associated lymph nodes (LNs), and other lymphoid sites from 78 individuals ranging from less than 1 year to 93 years of age. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-α+CD1c+) subsets was a function of tissue site and was conserved between donors. We identified cDC2 as the major mature (HLA-DRhi) subset in LNs with the highest frequency in lung-draining LNs. Mature cDC2 in mucosal-draining LNs expressed tissue-specific markers derived from the paired mucosal site, reflecting their tissue-migratory origin. These distribution and maturation patterns were largely maintained throughout life, with site-specific variations. Our findings provide evidence for localized DC tissue surveillance and reveal a lifelong division of labor between DC subsets, with cDC2 functioning as guardians of the mucosa. [Display omitted] •Human cDC1 and cDC2 subset distribution is a function of tissue site•cDC2s exhibit maturation and migration phenotypes in mucosal-draining lymph nodes•Mature cDC2s accumulate in lymph node interfollicular zones•Localized cDC subset distribution and maturation is largely retained over life Dendritic cells (DCs) function as tissue sentinels, but this role is difficult to study in humans. In this issue of Immunity, Granot et al. show through analysis of lymphoid and mucosal tissues that human DC maturation is tissue specific, associated with migration phenotypes, and predominantly observed among the cDC2 subset.