Opening a window on thymic positive selection: Developmental changes in the influence of cosignaling by integrins and CD28 on selection events induced by TCR engagement

How TCR and non-TCR signals are integrated by thymocytes to generate a deci sion to undergo either positive or negative selection remains incompletely understood, Recent evidence suggests that TCR signal transduction changes i ts quality during thymocyte maturation, but whether the contributions of va rious cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the po ssible selective roles of specific costimulatory pathways in induction of d ifferentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD 4(+)CD8(+) thymocyte differentiation as measured by CD69 up-regulation/core ceptor downmodulation was conducted in parallel with an analysis of inducti on of death. Using transfected cells varying in their surface display of IC AM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation wit hout substantially affecting induction of death among CD4(+)CD8(+) cells, a property that is lost as thymocytes mature further. In contrast, B7 engage ment enhances both cell activation and death in parallel. Based on these da ta, we propose that the high level of ICAM-1 on cortical epithelial cells p lays a special role in opening a window between TCR signaling for different iation vs death, permitting efficient initiation of positive selection on e pithelial ligands, In contrast, late CD28-dependent cosignaling on hemopoie tic cells in the medulla would help enforce negative selection by augmentin g the effects of TCR engagement by low levels of high affinity ligands.