Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC

The developmental fate of immature thymocytes is determined by the specificity of their T-cell antigen receptors (TCRs). Immature CD4+8+ thymocytes are positively selected to differentiate into mature T cells by recognition of peptides associated with major histocompatibility complex (MHC) encoded molecules on thymic epithelial cells. But neither the identity of molecules transducing positive selection signals nor the nature of the signals themselves is fully known. Here we report that direct ligation of TCR molecules by monoclonal antibodies specific for either clonotypic or CD3 chains can signal immature thymocytes to differentiate into mature CD4+8- T cells, even in the absence of MHC expression and MHC-dependent CD4 co-receptor signalling. Moreover, we show that TCR engagement induces positive selection signals only in the absence of TCR aggregation and that TCR aggregation is inhibitory for positive selection. Thus, low valency of TCR crosslinking is a critical parameter, distinguishing positive selection from other TCR-mediated signalling events.