T LYMPHOCYTES are predisposed to recognition of foreign protein fragments bound to cell-surface molecules encoded by the major histocompatibility complex (MHC)^{1, 2}. There is now compelling evidence that this specificity is a consequence of a selection process operating on developing T lymphocytes in the thymus^3–6. As a result of this positive selection, thymocytes that express antigen receptors with a threshold affinity for self MHC-encoded glycoproteins preferentially emigrate from the thymus and seed peripheral lymphoid organs. The specificity for both foreign antigen and MHC molecules is imparted by the α and β chains of the T-cell antigen receptor (TCR)^{7, 8}. Two other T-cell surface proteins, CD4 and CD8, which bind non-polymorphic regions of class II and class I MHC molecules respectively^{9, 10}, are also involved in these recognition events and play an integral role in thymic selection. In order to elucidate the developmental pathways of class II MHC-rest rioted T cells in relation to these essential accessory molecules, we have produced TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c and the E^k (class II MHC) molecule. The transgenic TCR is expressed on virtually all T cells in mice expressing ^k. The thymuses of these mice contain an abnormally high percentage of mature CD4⁺CD8⁻ cells. In addition, the peripheral T-cell population is almost exclusively CD4⁺, demonstrating that the MHC specificity of the TCR determines the phenotype of T cells during selection in the thymus.