Abstract
The thymus is unique in its ability to support the maturation of phenotypically and functionally distinct T cell sub-lineages. Through its combined production of MHC-restricted conventional CD4+ and CD8+, and Foxp3+ regulatory T cells, as well as non-conventional CD1d-restricted iNKT cells and invariant γδT cells, the thymus represents an important orchestrator of immune system development and control. It is now clear that thymus function is largely determined by the availability of stromal microenvironments. These specialized areas emerge during thymus organogenesis and are maintained throughout life. They are formed from both epithelial and mesenchymal components, and collectively they support a stepwise program of thymocyte development. Of these stromal cells, cortical, and medullary thymic epithelial cells represent functional components of thymic microenvironments in both the cortex and medulla. Importantly, a key feature of thymus function is that levels of T cell production are not constant throughout life. Here, multiple physiological factors including aging, stress and pregnancy can have either short- or long-term detrimental impact on rates of thymus function. Here, we summarize our current understanding of the development and function of thymic epithelial cells, and relate this to strategies to protect and/or restore thymic epithelial cell function for therapeutic benefit.
Highlights
While the bone marrow represents a major site of hemopoiesis, including hemopoietic stem cell development and maintenance as well as B-cell development, the generation of αβT cells relies upon the exit of lymphoid progenitors from the bone marrow and their entry into the thymus
Early thymus reconstitution following bone marrow transplant (BMT) does not require CCR7 and CCR9, as T cell progenitors deficient in both chemokine receptors generate DP thymocytes to an equivalent ability to WT cells in a competitive bone marrow chimera model [92]. These results indicate a transient period of time soon after BMT in which thymus settling occurs independently of CCR7 and CCR9
We still lack a clear understanding of how TEC populations are established during development, and how they change during the lifecourse
Summary
While the bone marrow represents a major site of hemopoiesis, including hemopoietic stem cell development and maintenance as well as B-cell development, the generation of αβT cells relies upon the exit of lymphoid progenitors from the bone marrow and their entry into the thymus. While these studies provide important new information on mTEC heterogeneity, it is not fully clear whether CCL21-expressing mTEC, that typically lie within the MHCIIloCD80lo (mTEClo) compartment represent directly progenitors of later mTEC stages, including mTEChi. immature mTEC progenitors are known to reside within the bulk mTEClo compartment, the expression of CCL21 by some of these cells suggests that they are already functionally mature [37], and so could be defined as a mature mTEC subset.
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