PRESELECTION THYMOCYTES ARE MORE SENSITIVE TO T-CELL RECEPTOR STIMULATION THAN MATURE T-CELLS

During T cell development, thymocytes which are tolerant to self-pepti des but reactive to foreign peptides are selected. The current model f or thymocyte selection proposes that self-peptide-major histocompatibi lity complex (MHC) complexes that bind the T cell receptor with low af finity will promote positive selection while those with high affinity will result in negative selection. Upon thymocyte maturation, such low affinity self-peptide-MHC ligands no longer provoke a response, but f oreign peptides can incidentally be high affinity ligands and can ther efore stimulate T cells. For this model to work, thymocytes must be mo re sensitive to ligand than mature T cells. Contrary to this expectati on, several groups have shown that thymocytes are less responsive than mature T cells to anti-T cell receptor for antigen (TCR)/CD3 mAb stim ulation. Additionally, the lower TCR levels on thymocytes, compared wi th T cells, would potentially correlate with decreased thymocyte sensi tivity. Here we compared preselection thymocytes and mature T cells fo r early activation events in response to peptide-MHC ligands. Remarkab ly, the preselection thymocytes were more responsive than mature T cel ls when stimulated with low affinity peptide variants, while both popu lations responded equally well to the antigenic peptide. This directly demonstrates the increased sensitivity of thymocytes compared with T cells for TCR engagement by peptide-MHC complexes.