Abstract A011: Tissue profiling reveals lifelong specialization of dendritic cell subsets in humans

Abstract

Abstract Conventional dendritic cells (cDCs) are a rare population of cells that sense the environment and whose major role is in initiating and controlling T cell immunity. The purpose of this study was to generate a map of cDC subset distribution and function over human life, which could serve as a framework for understanding and manipulating adaptive immunity. Current DC-based cancer therapies utilize DCs derived from blood monocytes, whose function may differ from tissue cDCs. We hypothesized that analysis of cDC dynamics in human tissues could uncover a hitherto uncharacterized division of labor between cDC subsets that could facilitate the development of more refined DC-based immunotherapies. To achieve this goal, we used flow cytometry and fluorescence imaging to investigate cDC frequency, maturation, migration and clustering in human peripheral and lymphoid tissues obtained from 60 healthy organ donors aged 3 months to 93 years. Utilizing a robust phenotyping scheme that combines well-established (CD1c, CD141) and tissue-optimized (CD13, CD64) markers, we were able to distinguish plasmacytoid DCs, CD14+ monocytic cells, and two cDC subsets in 14 different tissues. Frequency analysis revealed that anatomical (e.g. vascularization) and functional (e.g. antigen presentation) factors influenced tissue DC profiles, with blood-rich tissues such as lung and bone marrow dominated by CD14+ cells, and lymphoid tissues including lymph nodes (LNs) and gut-associated lymphoid tissues (GALT) enriched for CD13hi CD141+ cDC1. Parallel analysis of mucosal tissues and their draining LNs revealed that CD1c+ Sirp-α+ cDC2 displayed a propensity to undergo maturation, accumulating in T cell-rich clusters near LN B cell follicles. In contrast, cDC1 were mostly immature, and sporadically dispersed in LN T cell zones. cDC2 maturation varied between tissues, with the lung-draining LNs containing a higher proportion of mature cDC2 and larger cDC2 clusters. While cDC1 maturation was also slightly higher in the lung-draining LN, this was not associated with significant changes in cDC1 clustering. Remarkably, these maturation and migration patterns were sustained over at least 8 decades of life, shedding new light on the dynamic foundations of adaptive immunity in humans. Together, these results reveal a lifelong division of labor between human cDC subsets, with cDC1 continuously surveying T cell zones, and cDC2 patrolling peripheral tissues, dynamically maturing and aggregating in draining LN T cell-B cell border zones, where they are uniquely poised to coordinate adaptive immunity. Citation Format: Tomer Granot, Takashi Senda, Dustin Carpenter, Donna L. Farber. Tissue profiling reveals lifelong specialization of dendritic cell subsets in humans [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A011.