The Impact of Age-Associated Lymph Node Microenvironment Changes On Dendritic Cell:CD4+ T Cell Interactions During Germinal Center Initiation 2255775

Abstract

Abstract Introduction Germinal center (GC) formation in lymph node (LN) follicles is essential for generating high-affinity antibodies following infection or vaccination. This response in aging is impaired, resulting in smaller and fewer GCs that generate less abundant antibodies with reduced antigen affinities as compared to young adults. Early GC formation depends on dendritic cell (DC)-mediated activation of naïve CD4+ T cells, which differentiate into CD4+ T follicular helper (TFH) cells that drive B cell responses. Antigen-specific TFH induction is mediated by type 2 conventional DCs, which localize to the T:B cell interfollicular boundaries. Live-cell 2-photon microscopy has previously revealed that T cell priming by DCs occurs in distinct phases of lasting versus intermittent interactions, though the quality and duration of DC:CD4+ T cell interactions has not been characterized in aged hosts. We hypothesize that age-associated alterations in LN microenvironments disrupt these interactions, leading to impaired GC formation. Methods Young and aged mice were subcutaneously immunized in the flank with nitrophenyl hapten conjugated to ovalbumin in alum adjuvant, and naïve OT-II CD4+ T cells were adoptively transferred via retroorbital injection. 48 hours after immunization, draining LNs and naïve controls were analyzed by multiplex immunofluorescence microscopy to map the spatial organization of DCs and stromal elements. Results Structural mapping showed disrupted alignment of stromal networks, suggesting impaired spatial compartmentalization of the aged microenvironment. Moreover, within aged immunized mice the localization of DCs within the interfollicular region and T:B cell zone borders of the LNs were altered. Conclusion Our findings suggest age-associated disruption of the LN microarchitecture diminishes the quality of DC:CD4+ T cell interactions essential for initiating GCs. These insights highlight tissue microenvironmental remodeling as a key contributor to age-related immune decline. Funding Source NIH Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)