Thymocyte selection: not by TCR alone

During development of T cells in the thymus, T-cell receptor (TCR)-mediated recognition of self-MHC/self-peptide complexes on thymic stroma dictates the developmental fate of immature CD4+CD8+ (double positive) thymocytes. Intriguingly, TCR-generated intracellular signals can elicit two entirely different cellular responses in such thymocytes: apoptosis or further differentiation. The critical issue in understanding end-stage T-cell development is how TCR occupancy can be perceived in such markedly different ways by the TCR. Here, we review the cytoplasmic and nuclear events that result from TCR signaling during thymocyte selection. Studies aimed at distinguishing molecular components involved in positive selection (resulting in signals for further differentiation) and negative selection (resulting in apoptosis) will help solve this fascinating feature of T-lymphocyte biology. We also discuss how non-TCR-derived signaling might serve to fine tune the TCR-driven selection events in thymocytes. Central to this aspect of the conceptual framework needed to explain thymocyte selection is the observation that thymic antigen-presenting cells appear to be specialized in the induction of either positive or negative selection. Finally, we suggest a hypothesis that integrates the facts currently available on developing thymocytes, and which may serve to refine our exploration of unresolved issues in thymocyte selection. This hypothesis expands our focus to include signals from receptors other than TCRs as modulating and amplifying factors in thymocyte signaling.