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

Abstract

SUMMARY 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 aged <1–93years. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-α+CD1c+) subsets was a function of tissue site and 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.

Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation

“…This resource has enabled the study of immune cells to a depth and scope not previously possible—in 10–15 tissue sites from a single individual and from diverse individuals of all ages. Our studies have yielded consistent results on tissue-specific immune cell populations between disparate individuals (17, 19, 21, 23, 24); however, donors experience diverse COD and clinical states, raising the important question of whether clinical variations impact immune parameters.…”

“…We, along with our collaborators, have embarked on a multi-dimensional analysis of innate and adaptive immune cells in diverse tissue types (blood-rich, mucosal, lymphoid) from research-consented organ donors through a protocol and collaboration with our local organ procurement organization in the New York Metropolitan area, LiveOnNY (17–24). Using this resource, we have analyzed immune cell subset distribution and heterogeneity throughout the body and across the lifespan in tissues from over 100 individuals (19, 21, 23), revealing that T cell and dendritic cell subset composition and differentiation are specific to the tissue site, with some age-associated changes in specific compartments (17, 21, 23, 24).…”

“…Using this resource, we have analyzed immune cell subset distribution and heterogeneity throughout the body and across the lifespan in tissues from over 100 individuals (19, 21, 23), revealing that T cell and dendritic cell subset composition and differentiation are specific to the tissue site, with some age-associated changes in specific compartments (17, 21, 23, 24). While these findings suggest that organ donor tissues provide a reliable assessment of baseline immune responses, the extent to which clinical variations of the donors including circumstances of death or hospitalization, are affecting our results is not clear.…”

Human dendritic cell subsets: an update

“…The functional and anatomical classification of DC as ‘migratory tissue DC’ or ‘lymph node resident DC’ remains useful to define context. However, comparative gene expression studies have driven a robust classification of DC based primarily on lineage, that correlates with the differential expression of key transcription factors such as interferon regulatory factors 8 and 4 (IRF8 and IRF4) and performs well across all mammalian species . This recognizes plasmacytoid DC (pDC) and two types of ‘conventional’ or ‘classical’ DC (cDC) corresponding to the two subsets of myeloid DC previously defined by CD141 and CD1c expression in humans .…”

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines

“…The iDCs are close in phenotype to CD1c DCs and share most phenotypic markers with the exception of CD206. While it is recognized that all DC subsets may perform cross-presentation the lymph node resident CD8 + DCs in mice and CD141 + cDCs in humans are remarkably more efficient in this process and consequently capable of generating superior anti-tumor immunity [1,66,67]. …”