Regulatory T‐cell differentiation versus clonal deletion of autoreactive thymocytes

Abstract

The concept of clonal deletion of immune cells that carry an autoreactive antigen receptor was a central prediction of Burnet's clonal selection theory. A series of classical experiments in the late 1980s revealed that certain immature thymocytes upon encounter of 'self' are indeed removed from the T-cell repertoire before their release into the blood circulation. A second essential cornerstone of immunological tolerance, not anticipated by Burnett, has more recently surfaced through the discovery of Foxp3 + regulatory T cells (Treg). Intriguingly, it appears that the expression of an autoreactive T-cell receptor is a shared characteristic of T cells that are subject to clonal deletion as well as of those deviated into the Treg lineage. This is all the more striking as Treg differentiation for the most part branches off from mainstream CD4T cell development during thymocyte maturation in the thymus, that is, it may neither temporally nor spatially be separated from clonal deletion. This raises the question of how an apparently identical stimulus, namely the encounter of 'self' during thymocyte development, can elicit fundamentally different outcomes such as apoptotic cell death on the one hand or differentiation into a highly specialized T-cell lineage on the other hand. Here, we will review the T-cell intrinsic and extrinsic factors that have been implicated in intrathymic Treg differentiation and discuss how these parameters may determine whether an autoreactive major histocompatibility complex class II-restricted thymocyte is deviated into the Treg lineage or subject to clonal deletion.

Analysis of APC Types Involved in CD4 Tolerance and Regulatory T Cell Generation Using Reaggregated Thymic Organ Cultures

“…However, the factors that determine whether autoreactive T cells are deleted or converted to Tregs remain a matter of debate (4). Although most Foxp3 + cells are found among the SP4 thymocytes in the medulla, the thymic compartment in which Treg lineage commitment actually takes place is not clear (38,39).…”

“…Both thymic cortex and medulla were found to be suitable sites for Treg lineage commitment (39)(40)(41)(42). Current models for Treg development highlight either instructional control (external signals that drive the T cell lineage choice) or stochastic processes (T cell-intrinsic decisions) (4,43). In the context of the former, both thymic epithelial cells (42,44) and DCs (9,15) were found to support Treg development.…”

“…Hence, the thymus also produces regulatory T cells (Tregs) that are capable of regulating the remaining, potentially self-reactive cells outside the thymus (3). The developmental outcome for any individual T cell, ranging from deletion to lineage diversion (4,5), depends on many factors that are not fully understood.…”

Quantitative impact of thymic selection on Foxp3 + and Foxp3 − subsets of self-peptide/MHC class II-specific CD4 + T cells

“…This issue has been explored in mice transgenic for both a model antigen and a monoclonal TCR specific for a pMHCII ligand from that antigen. Deletion, anergy, and Treg cell generation have all been described as possible fates for the CD4 + T cells in these mice (2,12,13). However, the altered timing of TCR expression, the monoclonal nature of the TCRs in question, and the abnormal abundance of T cells expressing these TCRs have raised concerns about the physiological relevance of these findings (14)(15)(16).…”

To Be or Not to Be a T reg Cell: Lineage Decisions Controlled by Epigenetic Mechanisms

“…Antigen presentation by medullary antigen-presenting cells (APCs, namely medullary thymic epithelial cells and dendritic cell subsets) is sufficient to induce Foxp3 expression in developing thymocytes (17,18). However, the signals (T cell intrinsic or APC-derived) that promote or block T reg cell development have been incompletely studied so far (19). The picture changed with the study by Liu et al, which showed that PIAS1 inhibits the early steps of T reg cell development (7).…”