NEGATIVE AND POSITIVE SELECTION OF ANTIGEN-SPECIFIC CYTOTOXIC LYMPHOCYTES-T AFFECTED BY THE ALPHA-3 DOMAIN OF MHC-I MOLECULES

THE alpha-1 and alpha-2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-cell repertoire 1-3. Although the alpha-3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CD8 (refs 4, 5). CD8 is important in the selection of T cells as anti-CD8 antibody injected into perinatal mice interferes with this process 6. We previously used a hybrid class I molecule with the alpha-1/alpha-2 domains from L(d) and the alpha-3 domain from Q7b and showed that this molecule binds an L(d)-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes 7. Expression of this molecule in transgenic mice fails to negatively select a subpopulation of anti-L(d) cytotoxic T lymphocytes. In addition, positive selection of virus-specific L(d)-restricted cytotoxic T lymphocytes does not occur. We conclude that besides the alpha-1/alpha-2 domains of class I, the alpha-3 domain plays an important part in both positive and negative selection of antigen-specific cells.