What is the thymic microenvironment?
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.
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