A SIGNAL STRENGTH HYPOTHESIS OF THYMIC SELECTION - PRELIMINARY CONSIDERATIONS

During their differentiation, thymocytes are subjected to two rounds of selection. First, CD4(-)8(-) double-negative (DN) thymocytes with a functional TCR-beta chain express a alpha(-)beta(+) CD3 complex on their surface and, as a consequence, are selected to mature to the CD4(+)8(+) double-positive (DP) stage. This round ends after the initial proliferation of young DP thymocytes and is termed beta-chain selection. Second, DP thymocytes are selected on the basis of their alpha(+)beta(+) CD3 complex. This is termed repertoire selection and the cells are given three choices: death by neglect selection, death by positive selection, or deletion by negative selection. Using anti-CD3 epsilon mAb as invariant ligand, signals for beta-chain selection of DN cells including proliferation of DP cells do not require a Ca2+ response, are independent of CD3 zeta, and are only slightly impaired in the absence of p56(lck) (lck). Signals that induce positive selection of DP thymocytes require a partial Ca2+ response and CD3 zeta but are independent of lck. Deletion of DP thymocytes requires a full-blown Ca2+ response and both, CD3 zeta and lck. Thymic selection thus appears to be governed by a gradient of signal intensities.