Aged lymph node stromal microenvironment as a driver of immune function decline 2257900

Abstract

Immune system undergo profound age-associated changes underlying impaired immune function in response to infections, malignancies, and vaccines. While cell-intrinsic changes in lymphocyte are well recognized, emerging evidence indicates that degenerative changes in secondary lymphoid organs (SLO) microenvironment decisively contribute to immune decline. To define the molecular basis of these changes, we performed transcriptomic profiling and functional validation of non-hematopoietic lymph node stromal cells (LNSCs), which regulate lymphocyte homeostasis and orchestrate immune responses. Aging induces coordinated metabolic defects in fibroblastic reticular cells, a major stromal cell subtype, characterized by reduced expression of amino acid transporters and mitochondrial phosphate and ATP/ADP carriers. These alterations coincided with a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, accompanied by mitochondrial dysfunction and a reduction in their ability to maintain T cells. Functionally, aged LNSCs exhibited impaired proliferation and expansion of the reticular network during West Nile virus and herpes simplex virus type 1 infections, resulting in diminished and hypofunctional antigen-specific CD8+ T cell responses. Restoring mitochondrial quality through mitophagy induction enhanced the ability of aged LNSCs to support naïve T cells in vitro. Ongoing studies aim to identify upstream cues driving these stromal metabolic defects and to leverage FRC-specific genetic models to dissect their role in functional immune decline with age. Together, these results suggest that age-related mitochondrial and metabolic changes in the lymph node stromal microenvironment contribute to T cell immune function. n/a Lymphocyte Differentiation and Peripheral Maintenance (LYM)