The age-related changes in lymph node stromal cells underlie defects in peripheral T cell maintenance and immune function decline in old mice.

Abstract

Abstract Older adults are more vulnerable to infection and cancer, and poorly respond to vaccination. The structural stromal cells in the lymph nodes (LN) are essential regulators of T cell homeostasis and immune response. However, how does aging of LN stromal cells contribute to T cell maintenance defects and functional immunity is incompletely understood. Here we used single cell RNA-Seq of purified stromal cells from adult (3mo) and old (21mo) peripheral LN of C57BL/6 mice to characterize the age-related transcriptional differences in major stromal cell subsets. Our data revealed the enrichment of CCL19 hiand CCL19 lowwhile diminution of Nr4a1 +and Inmt +FRC in old LN. The enriched FRC in old LN exhibited a gene signature of cellular and oxidative stress response, mitochondrial defects, and negative regulation of immunity. The ex vivo functional characterization revealed that old LN stromal cells exhibit elevated mitochondrial reactive oxygen species coupled with increased mitochondrial mass and reduced membrane potential, indicative of mitochondrial defects during the senescence. Interestingly, these defects are observed in older but not mid-age LN. Furthermore, in vitro co-culture of LN stromal cells and purified naive T (T N) cells showed that old LN stromal cells poorly support CD8 T Ncell survival. Finally, boosting the function of old LN stromal cells using agonistic anti-LTbR or mitigating oxidative stress using N-Acetyl Cysteine reversed this effect, via stabilization of BCL2 in T Ncells. Thus, these results suggest that age-related adverse changes in LN stromal cells contribute to defects in maintenance of T Ncells, and highlight that these defects could be reversed to restore T Ncell homeostasis and functional immunity. This work is supported by grants from NIH (P01 AG052359 and R37 AG020719) to Dr. Janko Nikolich-Zugich.