During development of T cells in the thymus, T-cell receptor (TCR)-med
iated recognition of self-MHC/self-peptide complexes on thymic stroma
dictates the developmental fate of immature CD4(+)CD8(+) (double posit
ive) thymocytes. Intriguingly, TCR-generated intracellular signals can
elicit two entirely different cellular responses in such thymocytes:
apoptosis or further differentiation. The critical issue in understand
ing end-stage T-cell development is how TCR occupancy can be perceived
in such markedly different ways by the TCR. Here, we review the cytop
lasmic and nuclear events that result from TCR signaling during thymoc
yte selection. Studies aimed at distinguishing molecular components in
volved in positive selection (resulting in signals for Further differe
ntiation) and negative selection (resulting in apoptosis) will help so
lve 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 conceptu
al framework needed to explain thymocyte selection is the observation
that thymic antigen-presenting cells appear to be specialized in the i
nduction of either positive or negative selection. Finally, we suggest
a hypothesis that integrates the facts currently available on develop
ing thymocytes, and which may serve to refine our exploration of unres
olved issues in thymocyte selection. This hypothesis expands our focus
to include signals from receptors other than TCRs as modulating and a
mplifying factors in thymocyte signaling.