Figure 1. Age-related changes in the stromal cells and lymph node structure and organization.

Lymph node stromal cell compartments form the structure, organization, and compartmentalization of the lymph node, and significantly contribute to the homeostatic maintenance of peripheral naïve T cells. The lymph nodes in aged mice and humans exhibit several degenerative changes, characterized by loss of size and total cellularity, capsule thickening, impaired cellular compartmentalization, and accumulation of collagen and other extracellular matrix components (fibrosis) and adipocytes (lipomatosis). Specific defects that contribute to impairment in homeostatic maintenance of lymphocytes involve- (1) Impairment in the ability of T cell zone fibroblastic reticular cells (TRC) to maintain naïve T cells. This issue may be triggered by the loss of FRC/TRC structural integrity, dysregulation of homeostatic chemokines (CCL19 and CCL21), and fibrosis and other structural stiffness issues that may hamper the bioavailability of trophic and homeostatic molecules [19, 21, 61, 68]. (2) Recent evidence from aging human lymph node studies indicates that medullary reticular cells located in the medullary region are highly prone to undergo transdifferentiation into adipocytes [102], which may in part explain increased lipomatosis often found in the old lymph nodes [103]. Such structural change has broader consequences, such as loss of lymphatic integrity and function and aberrant plasma cell and macrophage maintenance in the medulla [102]. (3) Chemokine dysregulation in the aged mouse lymph nodes can mislocalize follicular helper T cells to the dark zone of the germinal center [131], which affects the FDC proliferation and quality of germinal center response during vaccination [64, 131]. (4) Similarly, alteration in homeostatic chemokine gradient is thought to underlie the phenotype of diffused T and B cell compartments often seen in the old human and mice lymph nodes [68, 99, 100, 118]. (Created with BioRender.com)