Age-associated changes to lymph node fibroblastic reticular cells

Abstract

Abstract The decreased proportion of antigen-inexperienced, naïve T cells is a hallmark of aging in both humans and mice, and contributes to reduced immune responses, particularly against novel and re-emerging pathogens. Naïve T cells depend on survival signals received during their circulation among the lymph nodes by direct contacts with stroma, in particular fibroblastic reticular cells. Gross changes to the architecture of the lymph nodes have been described, but it is unclear how lymph node stroma are altered by aging, and whether these changes contribute to reduced naïve T cell maintenance. Here, we visualized naïve T cell migration in the aged lymph node using 2-photon microscopy and determined that T cell motility is impaired when in proximity to fibrotic deposition. Adoptive transfer of young naïve T cells into young or aged hosts revealed reduced homeostatic turnover in the aged host, supporting the role of T cell-extrinsic mechanisms that regulate their survival. Further, we determined that development of early fibroblastic reticular cells of the lymph node stroma is impaired, which can contribute to declining levels of naïve T cell survival factors. Thus, our study addresses the controversy as to whether aging impacts the composition lymph node stroma and supports a model in which impaired differentiation of lymph node fibroblasts inhibits the interactions necessary for naïve T cell homeostasis.