Immunosenescence has been well described in both human and a variety of animal species and has an important influence on changes in immune function. Although several mechanisms may be operating to explain the alterations in immune function with age, one factor that has attracted significant attention has been the progressive age-dependent involution of the thymus. Hitherto, most studies of thymus have focused only on thymocytes. We have now taken advantage of a well-defined panel of monoclonal antibodies (mAbs called MTS) that recognize and characterize the thymic miroenvironment, including epithelial and nonepithelial elements. Recent data using these MTS mAbs have disclosed significant abnormalities in the thymic cortex in models of murine lupus including the unusual appearance of medullary-type epithelial cells in the cortical areas and the presence of epithelial free spaces or ‘cortical holes’. In this study, we investigated age-related changes in the thymic microenvironment in 12-month-old C3H/HeJ, C57BL/6 and BALB/c mice. Controls included thymus from young 4-to 6-week-old mice as well as 6-month-old BALB/c mice. As expected, the thymus of all 12-month-old mice manifested normal and distinctive separation of cortical and medullary epithelium. However, unlike younger mice, the 12-month-old mice had severe changes in these regions. For example, in older mice, the cortex and medulla were diffusely irregular and atrophic and had a poorly defined cortico medullary junction; the former having small disrupted epithelial networks, and the latter containing clusters of atrophic cells. Moreover, the extracellular matrix was increased and contained large irregularly shaped clusters. Interestingly, the thymus of 6-month-old mice expressed some changes within the medullary epithelium and the extracellular matrix, but the cortical epithelium remained unchanged. These age-related degenerative changes in the thymic microenvironment differ significantly from the abnormalities identified in autoimmunity and may be a factor in immunosenescence.

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It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcph me/Hcph me, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice.