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 p56lck (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.
Eichmann
K
K
Max-Planck-Institut für Immunobiologie, Freiburg, Germany.
D017252:CD3 Complex / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D018448:Models, Immunological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012641:Selection, Genetic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000276:immunology*
D017252:CD3 Complex; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium