What is the thymic microenvironment?

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The thymus is the primary immunological organ that is responsible for the production of self-restricted, self-tolerant T cells. It consists of developing T cells, or thymocytes, supported by a complex cellular network containing a variety of resident cell types, including thymic epithelial cells (TEC), dendritic cells, vasculature, and mesenchymal cells. These cell types comprise multiple functional microenvironments that restrict immigrating lymphoid progenitor cells (LPCs) to the T cell fate, then direct and support these thymocytes to develop from immature progenitors into mature cells, shaping this emerging repertoire such that it is both self-tolerant (will not attack the body's own cells) and self-restricted (recognizes peptide antigens in the context of 'self' MHC). The thymus is built during embryonic stages and maintained postnatally through both thymic epithelial cell-autonomous mechanisms and complex intercellular crosstalk interactions. During development and in the steady-state thymus, thymic epithelial cells (TECs) produce growth, differentiation and survival factors required for thymocyte maturation and present self-peptide/MHC complexes that mediate positive or negative selection. Thus, T cell development in the thymus is not a cell autonomous process, but requires interactions with the thymic microenvironments that provide signals for their survival, proliferation, and differentiation. A steady supply of naïve T cells is essential for optimal function of the peripheral adaptive immune system and is directly correlated with thymus organ size, and with the structure and function of the thymic microenvironment.  Failure of these events results in immunodeficiency or autoimmunity.

In the thymus, lymphoid progenitor cells undergo a series of progressive differentiation steps via interactions with the non-lymphoid stromal cell microenvironments that they encounter during a stereotypical migration path through the thymus organ. Unlike the bone marrow, self-renewing hematopoietic stem cells (HSCs) do not reside in the thymus, and so there is no HSC microenvironmental stem cell "niche". However, there is evidence for the existence of one or more types of thymic epithelial progenitor or stem cells in the postnatal thymus, that, if they exist, presumably reside in specific microenvironments of their own. Thus, there is not really a single thymic microenvironment, but multiple ones, each of which promotes specific events in T cell differentiation, or supports stem or progenitor cells that maintain the thymic epithelial component of the stromal environment. The question of the nature of the thymic microenvironment is thus a complex one that remains poorly understood. In this chapter, we will review aspects of the current literature addressing the fetal development, postnatal function, and aging-related decline of the thymic cellular microenvironment(s). We will discuss the microenvironmental components with an emphasis on TEC subsets required for thymocytes to differentiate into functional T cells, and address the question of whether thymic epithelial stem or progenitor cells maintain these microenvironments.