Functional and Homeostatic Impact of Age-Related Changes in Lymph Node Stroma

Abstract

Adults over 65 years of age are more vulnerable to infectious disease and show poor responses to vaccination relative to those under 50. A complex set of age-related changes in the immune system is believed to be largely responsible for these defects. These changes, collectively termed immune senescence, encompass alterations in both the innate and adaptive immune systems, in the microenvironments where immune cells develop or reside, and in soluble factors that guide immune homeostasis and function. While age-related changes in primary lymphoid organs (bone marrow, and, in particular, the thymus, which involutes in the first third of life) have been long appreciated, changes affecting aging secondary lymphoid organs, and, in particular, aging lymph nodes (LNs) have been less well characterized. Over the last 20 years, LN stromal cells have emerged as key players in maintaining LN morphology and immune homeostasis, as well as in coordinating immune responses to pathogens. Here, we review recent progress in understanding the contributions of LN stromal cells to immune senescence. We discuss approaches to understand the mechanisms behind the decline in LN stromal cells and conclude by considering potential strategies to rejuvenate aging LN stroma to improve immune homeostasis, immune responses, and vaccine efficacy in the elderly.

Compromised steady‐state germinal center activity with age in nonhuman primates

“…We observed significant differences of GC activity between young and old NHP LNs. The dark and the light zone were largely indistinguishable in many of the old follicles, in line with studies showing that the microenvironment of the LN is disrupted with age due to disruption of the FDCs, FRCs, and other stromal cells (Thompson et al, ). This altered GC organization was associated with significantly lower normalized numbers of Tfh and CD20 hi Ki67 hi GC B cells, suggesting disrupted mutual regulation between Tfh and GC B cells (Baumjohann et al, ) that could result in impaired steady‐state GC reactivity in old NHP LNs.…”

“…Interrupting the cross‐talk between Tfh and B cells results in impaired GC formation and pathogen‐specific B‐cell responses in aged mice (Sage et al, ). Furthermore, mouse models have shown that aging impacts many of these populations including fibroblastic reticular cells (FRCs), a cellular network crucial for the survival of naïve T cells and trafficking of T cells within the extra follicular areas (Thompson, Smithey, Surh, & Nikolich‐Zugich, ), FDCs, vital for GC organization and antigen presentation to B cells (Aydar, Balogh, Tew, & Szakal, ), tissue macrophages, and Tfh and B cells (Eaton, Burns, Kusser, Randall, & Haynes, ; Turner & Mabbott, ).…”

SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes

“…In fact, lymph nodes are in charge of both maintenance and coordination of new immune responses necessary to control viruses such as SARS-2. Lymph nodes undergo dramatic age-related changes in the final third of life, becoming less able to maintain naïve T cells (Thompson et al 2017) and to coordinate new immune responses to emerging infections Moreover, the T cells that do remain do not move quickly enough to meet innate immune cells when the infection strikes , which could be a consequence of dysregulation in chemokines that guide T cell migration. Innate immune cells themselves do not get activated by infection as efficiently in mice ) and humans .…”

Deconstructing Immune Microenvironments of Lymphoid Tissues for Reverse Engineering

“…The dependence of immunity on the immune microenvironment that is constructed by the supporting cellular players is apparent. Furthermore, there are reports on the negative effects of pathological perturbation of LN stroma on immune function . An appropriate and optimum amount of collagen and thickness of the collagen bundles of the reticulum network is important for lymphoid architecture and function.…”