Architectural changes in the thymus of aging mice

Abstract

SummaryAge-associated thymic involution is one of the most dramatic and ubiquitous changes in the immune system, although the precise mechanisms involved still remain obscured. Several hypotheses have been proposed incorporating extrinsic and intrinsic factors, however, changes in the thymic microenvironment itself is one of the least investigated. We therefore decided to undertake a detailed histological examination of the aging thymus in order to elucidate possible mechanisms of thymic atrophy. This investigation provides insight into the changes within the murine thymus with age, demonstrating a new approach to quantify protein expressional differences while preserving the thymic architecture. There is a decline in expression of thymic epithelial cell-specific makers and an increase in fibroblast content in the aging mouse thymus. This is concurrent with a disorganization of the thymic compartments, a morphological transformation within the epithelial cells and alterations of their archetypal staining patterns. Furthermore, this is linked to a rise in apoptotic cells and the novel finding of increased senescence in the thymus of older mice that appears to be colocalized in the epithelial compartment. These changes within the thymic epithelial cells may be in part accountable for thymic atrophy and responsible for the decline in T-cell output.

Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner

“…In addition, lacZ/lacZ and lacZ/nu thymi showed reduced UEA-1 ϩ mTECs within the K14 ϩ medullary regions ( Figure 3E). All of these TEC and stromal organization phenotypes were similar to those seen in the aged wild-type thymus 34,35 (Figure 3D,F). …”

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…Next, we determined whether premature involution in NOD is associated with altered thymic architecture (24). At 3 mo, NOD and B6 mice have similar thymic organization as judged by keratin staining and cortical/medullary restricted markers (Supplemental Figs.…”

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…. Cell extrinsic: Rescue of thymus involution by androgen depletion (Sutherland et al, 2005) Cell extrinsic: Impaired lymphopoiesis depending on recipient age (Labrie et al, 2004;Stephan et al, 1998) Reduced thymocyte output and altered structure of the aging thymus (Aw et al, 2008;Gray et al, 2006) (Sutherland et al, 2005) Cell extrinsic: Appears to be dominant mechanisms, HSCs of young wildtype show skewing after transplantation into old Terc -/-mice with dysfunctional telomere, but not after transplantation in age matched wildtype mice. Premature involution of the thymus The contribution of cell intrinsic or extrinsic mechanisms are largely unknown.…”