Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production

Abstract

The most conspicuous period of cellular proliferation and differentiation occurs during the embryonic stage of development. In some cell lineages, however, including T lymphocytes, this process must continue postnatally and throughout life. Under ordinary circumstances, postnatal T-cell production occurs in the thymus, and can be separated into five functional phases. The first is recognition of thymus-derived recruitment signals by multilineage progenitors in the bloodstream, followed by their extravasation and entry into the organ. Second is the lymphopoietic process, i.e. the expansion of this small number of blood-derived progenitors to produce the raw materials for all subsequent phases. Third is the screening of these cellular products for the ability of their T-cell receptors to appropriately recognize major histocompatibility/peptide ligands, i.e. positive and negative selection. Fourth is functional maturation, a process that follows but is distinct from positive selection. Finally, cells that successfully undergo all of the prior processes must be induced to leave the thymus and enter the peripheral lymphoid pool. From the above, it can be seen that all the hematopoietic components of the thymus are transient, with uncommitted progenitors entering and lineage committed progeny being exported or removed. This process reveals a subtle but critically important fact about the nature of the thymus, namely that the functional components of the thymus are not the hemato-lymphoid cells, but rather the stable (stromal) elements that induce their differentiation. Understanding the nature of these stromal elements, and the signals they deliver to nascent T lymphocytes, is therefore critical not only for understanding how T lymphocytes are produced normally but, by analogy, what goes wrong in congenital, acquired, or age-associated deficiencies in T-lymphocyte production.