Positive and negative thymocyte selection

Abstract

T cells differentiate from CD4-CD8- (DN) precursor to mature CD4+ or CD8+ (SP) thymocytes through the CD4+CD8+ (DP) stage. Immature thymocytes express pre-TCR complex composed of pT alpha and TCR beta chains, which plays a role in allelic exclusion of TCR beta and promotion from DN to DP transition. During the DP stage, thymocytes are subjected for selection, either expansion/differentiation into SP cells (positive selection) or deletion (negative selection). The level of TCR signals, which is mainly affected by the avidity between TCR and self-peptide/MHC and the contribution of coreceptors (CD4, CD8), determines the fate of thymocytes. The difference of avidity may result in distinct kinetics when signaling machinery assembles with TCR. As TCR signals increase either by high expression of TCR/coreceptors or higher avidity, the fate of thymocytes changes from default death (no selection) to positive selection and then negative selection. Although signaling pathways to discriminate these selections are largely unknown, ZAP-70 and Lck are important for both processes, whereas calcineurin and MAPK pathway play crucial roles in positive selection. TCR signals also affect the CD4/CD8 lineage commitment. The requirements for the two lineages are different. Differentiation of CD4 SP thymocytes requires stronger TCR signals, while special signals such as Notch-mediated signal are necessary for development of CD8+ cells.