Thymocyte selection: not by TCR alone

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Abstract
Summary: During development of T cells in the thymus. T‐cell receptor (TCR)‐mediated recognition of self‐MHC/self‐peptide complexes on thy‐mic stroma dictates the developmental fate of immature CD4+CD8+ (double positive) thymocytes. Intriguingly, TCR‐generated intracellular signals tan 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 ac 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‐Iymphocyte 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.