Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

Abstract

The stromal microenvironment in the thymus is essential for generating a functional T cell repertoire. Thymic epithelial cells (TECs) are numerically and phenotypically one of the most prominent stromal cell types in the thymus, and have been recognized as one of most unusual cell types in the body by virtue of their unique functions in the course of the positive and negative selection of developing T cells. In addition to TECs, there are other stromal cell types of mesenchymal origin, such as fibroblasts and endothelial cells. These mesenchymal stromal cells are not only components of the parenchymal and vascular architecture, but also have a pivotal role in controlling TEC development, although their functions have been less extensively explored than TECs. Here, we review both the historical studies on and recent advances in our understanding of the contribution of such non-TEC stromal cells to thymic organogenesis and T cell development. In particular, we highlight the recently discovered functional effect of thymic fibroblasts on T cell repertoire selection.

Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

“…As a primary lymphoid organ, thymus plays an indispensable role in the establishment of central immune tolerance (Anderson and Takahama, 2012;Abramson and Anderson, 2017). Among the thymic stromal cells, thymic epithelial cells (TECs) provide a special microenvironment for the survival, development and maturation of thymocytes to the development of immunological competent T lymphocytes which can recognize foreign antigens rather than self-antigens (Sun et al, 2014;Abramson and Anderson, 2017;Nitta and Takayanagi, 2020). TECs include cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) (Alawam et al, 2020).…”

Developmental dynamics of the neural crest-mesenchymal axis in creating the thymic microenvironment

“…S3). Patterning of the extracellular matrix is critical in supporting thymic organogenesis, suggesting that thymic mesenchymal diversity will likely have a broad impact on thymic in vivo function (8). Single cell sequencing of human thymus tissue identifies a heterogeneity among NETS that is similar to the variance observed in mice and thus constitutes a trans-species phenomenon (37,52).…”

“…S3). Patterning of the extracellular matrix is critical in supporting thymic organogenesis, suggesting that thymic mesenchymal diversity will likely have a broad impact on thymic in vivo function ( 8 ).…”

“…This critical function of mesenchymal cells is accomplished via the production of extracellular matrix components, morphogens and key growth factors (3,4,7). Hence, the thymic mesenchyme is indispensable for the organ's correct formation and function (1,7,8). Fibroblasts constitute the largest component of the non-epithelial thymus stroma.…”

“…Fibroblasts constitute the largest component of the non-epithelial thymus stroma. (NETS) Though first described as distinct cell type over 150 years ago, the specific contributions of fibroblasts to organ formation, maintenance and function have only recently begun to be unraveled ( 8 ). Utilizing single-cell genomic technologies for the comparison of diverse tissues, fibroblasts were noted to display a significant heterogeneity with both cross-organ communalities and tissue-specific differences ( 9 ).…”