Age-Associated Changes to Lymph Node Fibroblastic Reticular Cells

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. Macroscopic changes to the architecture of the lymph nodes have been described, but it is unclear how lymph node stroma are altered with age, and whether these changes contribute to reduced naïve T cell maintenance. Here, using 2-photon microscopy, we determined that the aged lymph node displayed increased fibrosis and correspondingly, that naïve T-cell motility was impaired in the aged lymph node, especially in proximity to fibrotic deposition. Functionally, adoptively transferred young naïve T-cells exhibited reduced homeostatic turnover in aged hosts, supporting the role of T cell-extrinsic mechanisms that regulate their survival. Further, we determined that early development of resident fibroblastic reticular cells was impaired, which may correlate to the declining levels of naïve T-cell homeostatic factors observed in aged lymph nodes. 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 and increased fibrosis inhibits the interactions necessary for naïve T cell homeostasis.

The influence of three-dimensional structure on naïve T cell homeostasis and aging

“…However, we found no effect of FRC aging on naïve T cell phenotype or survival, implying that both the positive and negative signals coming from FRCs are unaffected by age. Similarly, a detailed analysis of lymph node FRCs revealed similar T cell-suppressive function of FRCs from young and older mice (Masters et al, 2019;Kwok et al, 2022). Alternatively, there is evidence of LN architecture breaks down.…”

“…Alternatively, there is evidence of LN architecture breaks down. In mice and non-human primates, LNs have increased collagen deposition with age, which could affect structural integrity ( Kwok et al, 2022 ). In human LNs, multiple changes have also been documented that could affect structural integrity and stromal cell behavior, such as fibrosis and lipomatosis ( Cakala-Jakimowicz et al 2021 ).…”

Stromal transdifferentiation drives lymph node lipomatosis and induces extensive vascular remodeling

“…Although LN lipomatosis is a common phenomenon in the elderly, there are only a few published articles on LN lipomatosis [5,6], and both the underlying mechanisms and consequences are unknown. One reason for the lack of mechanistic data is that spontaneous LN lipomatosis rarely is seen in aging mice, where fibrosis instead dominates ( [31,32]. We here choose to approach the questions behind the pathology by in situ analysis of human LNs.…”

Distinct Heterogeneity in the Naive T cell Compartments of Children and Adults

“…( 26 ) In the context of T cell aging, multiple studies in animal models reveal increased fibrosis in lymph nodes with age is associated with impaired T cell homeostasis. ( 27 , 28 ) Thus, investigation into the crosstalk between naive T cell state and the microenvironment is of great interest.…”