TCR-Independent Development of Pluripotent T-Cell Precursors

Abstract

The various contributions to this book are intended to serve as a collection of opinions based on contemporary knowledge. The opinion the authors will seek to illustrate here, that T-cell differentiation is not driven by T-cell receptor (TCR) expression, is an unconventional view and in reality, will probably need to be tempered by nuance and circumstance. Nonetheless, most of the data that have lead to the conventional view (i.e., T-cell development that is directed by TCR expression) could be reinterpreted to support the proposal that TCR expression, although absolutely required for T-cell survival and function, does not drive differentiation, but rather, facilitates survival. It is noteworthy to point out that many of the early stages of intrathymic differentiation occur prior to any TCR gene recombination, illustrating the concept that differentiation can occur without a TCR. Further, what immunologists refer to as “selection” is, in fact, a common function among developing tissues: survival, mediated by the absolute requirement for a given gene product at some specific point during development. Given the absence of a required gene product, as can happen in the mutation of any gene, the affected cell dies. Nevertheless, other developmental events occur independently of such a defect, up to and including the point where its essential function is required. In the case of the TCR, the frequency of such “mutations” is abnormally high, because of the random nature of the recombination and recognition processes. As will be discussed, it is nevertheless conceivable and useful, to view T-cell development as occurring independently of TCR expression, with TCR+ cells surviving the developmental process, whereas TCR− cells die. Likewise, an attempt will be made to make the similar point that TCR-α/β versus γ/δ expression on a given cell does not induce T lineage divergence; rather, it facilitates the survival of those cells that express the appropriate TCR isotype. Finally, it is important to state that the concepts presented here are directed toward an understanding of T-cell development in the adult murine thymus. Fetal T-cell development, although similar to that of the adult, differs in many important ways (1,2), and extrapolation between these models may not be accurate.KeywordsGene RearrangementLineage CommitmentThymocyte DevelopmentImmature ThymocyteAllelic ExclusionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.