Differentiation of alpha beta T cell receptor (TCR)-expressing T cells
involves an obligatory interaction with self-major histocompatibility
complex (MHC) molecules in the thymus. This process, called positive
selection, both rescues thymocytes from programmed cell death and indu
ces their differentiation into mature T cells. Another critical event
in thymic development is to prevent maturation of hazardous autoreacti
ve T cells; thus, mechanisms exist to eliminate T cells with self-reac
tive receptors (negative selection). How can these two pathways be dis
tinguished? This question, which has long taxed immunologists, is more
apposite because many features of the interactions in positive and ne
gative selection are shared: Both processes are exquisitely MHC-allele
specific, they involve MHC-bound peptide recognition, and employ at l
east some overlapping signal transduction pathways. However, resolutio
n of this paradox has become much more feasible with the advent of pow
erful systems for withdrawing and reconstituting individual components
involved in positive selection. This review describes recent advances
in our understanding of the cells, receptors, ligands, and signaling
pathways involved in this process. A pivotal part of this puzzle is th
e basis for discrimination between TCR ligands that induce positive vs
negative selection. Recent work suggests that the peptide/MHC ligand
for positive selection may bind with low avidity to the TCR. The impli
cations of these data for the nature of T cell recognition during posi
tive selection are discussed below.