Limiting TCR expression leads to quantitative but not qualitative changes in thymic selection

Thymic selection is controlled in part by the avidity of the interaction be tween thymocytes and APCs, In agreement, the selective outcome can be modul ated by altering the expression levels of selecting ligands on APCs, Here w e test the converse proposition, i.e., whether changing TCR levels on thymo cytes can alter the selective outcome. To this end, we have generated mice in which all thymocytes express two transgenic TCRs simultaneously (dual TC R-expressing (DTE) mice), the class I-restricted HY TCR and the class II-re stricted AND TCR, Due to mutual dilution, surface expression levels of the two individual transgenic TCRs are diminished in DTE relative to single TCR -expressing mice, We find that thymic selection is highly sensitive to thes e reductions in TCR surface expression. Positive selection mediated by the AND and HY TCRs is severely impaired or abolished, respectively. Negative s election of the HY TCR in male DTE mice is also partly blocked, leading to the appearance of significant numbers of double positive thymocytes. Also, in the periphery of male, but not female, DTE mice, substantial numbers of single positive CD8(bright) cells accumulate, which are positively selected in the thymus but by a highly inefficient hemopoietic cell-dependent proce ss, Overall our results favor the interpretation that the outcome of thymic selection is not determined solely by avidity and the resulting signal int ensity, but is also constrained by other factors such as the nature of the ligand and/or its presentation by different subsets of APCs.