Role of the Thymus in T lymphocyte reconstitution

Normal events in T-cell development. T lymphocyte development begins early in fetal life and continues well into adulthood. Pluripotential hematopoietic stem cells migrate from the bone marrow to the thymus and through interaction with stromal cells, and in the presence of various soluble factors, lose their pluripotentiality committing to T-cell differentiation. Rearrangement of germline DNA juxtaposes genes of the T cell receptor (TCR) to produce antigen receptors with a vast number of different specificities. Thymocytes displaying different receptor specificities are subjected to both positive and negative selection, to ensure that only T cells reactive with foreign antigenic peptides seen in the context of self-MHC molecules are permitted into the periphery. Cells that fail this process of “education” are deleted. As a result, only a small percentage of the thymocytes generated actually leave the thymus as T cells, to join the peripheral pool. These emigrant T cells express CD45RA and constitute a population that does not increase by division, whose constituent T cells are called “naive” until they meet the antigen for their specific receptor. This interaction leads to activation, clonal expansion, and eventual conversion to the effector/primed/memory (CD45RO) phenotype. Several reports suggest that some of these cells later revert to a phenotype similar to that of naive T cells, prompting attempts to identify the true naive thymic emigrants using a variety of phenotypic markers. Delineation between these populations would be beneficial because various physiological, pathological, and therapeutic conditions such as aging, immunosuppressive therapy (radio/chemotherapy), infection with human immunodeficiency virus (HIV)-1, and bone marrow transplantation (BMT) are associated with T-cell depletion. Immune reconstitution represents a challenge in these cases, and assessing the central role of the thymus is important in determining the kinetics of reconstitution (Table 1).