Age-driven Dysregulation of murine Dendritic Cells is controlled by cell-intrinsic and extrinsic effects

Abstract

Aging is associated with chronic, low-grade inflammation and progressive immune dysfunction. However, the current understanding of age-associated changes in dendritic cells across tissues is scarce. Studies exploring ageing-associated changes in dendritic cells (DCs) have reported either a general decline in the overall DC compartment or subset-specific alterations affecting cDC1, cDC2, and pDC populations across spleen, lung and liver, underscoring the considerable inconsistencies across tissues and studies. To underpin whether age-associated changes are extrinsic or intrinsic we investigated DCs across bone marrow, six peripheral tissues and in in vitro bone marrow derived DC cultures to examine the effects of aging on DC-poiesis, tissue distribution, and cellular states related to DC functionality and activation. We discovered that aging selectively alters DC development in the bone marrow by reducing cDC progenitor populations while preserving pDC-poiesis. In peripheral tissues, however, age-associated changes in DC homeostasis were strongly tissue-dependent. The most significant shifts in cDC1 and cDC2 frequencies occurred in barrier tissues, such as the lung and small intestine. In contrast, the spleen and liver exhibited more limited or variable changes. These quantitative alterations were accompanied by tissue-specific changes in phenotypic and activation-associated markers, including CD24, CD103, CD11b, MHCII, and CD86. Single-cell transcriptomic analyses of senescent p21-expressing DC across tissues and subsets indicated localized inflammatory states that aligned with local macrophage populations, pointing toward cell-extrinsic niches that contribute to local age-associated dysfunction. Notably, aged bone marrow retained the capacity to efficiently generate DCs in in vitro Flt3L cultures, and antigen-presenting function of BMDC to CD4 and CD8 T cells was maintained, pointing towards preserved cell-intrinsic functions, albeit subset-specific differences in activation and inhibitory receptor expression in response to different pattern-recognition receptor agonists. Collectively, our findings indicate that aging does not superimpose a uniform alteration module to the DC compartment across tissues, but instead promotes selective alterations in DC ontogeny and tissue-specific remodeling of DC phenotypes and cellular states.