Affinity of thymic self-peptides for the TCR determines the selection of CD8(+) T lymphocytes in the thymus

Experiments with synthetic antigen peptides have suggested that a critical parameter that determines the developmental fate of an immature thymocyte i s the affinity of interaction between TCR and self-peptide/MHC expressed on thymic stromal cells. To test the physiological relevance of this model fo r thymocyte development, we determined the affinity of the anti-MY TCR (B6. 2.16) expressed on CD8(+) cells for thymic self-peptide/H-2D(b) tetramers, then examined the ability of these self-peptides to determine the outcome o f B6.2.16 CD8 cell selection in the thymus. The B6.2.16 TCR bound the male HY self-antigen with high affinity. Thymic self-peptides, which are highly abundant on the surface of thymic epithelial cells, bound the B6.2.16 Ton w ith low affinity. The ability of self-peptides to trigger positive or negat ive selection of B6.2.16 CD8 cells in cultured fetal thymi was determined b y the relative affinity of self-peptide/H-2D(b) for the B6.2.16 TCR. High-a ffinity binding of the HY self-peptide resulted in B6.2.16 TCR complex zeta chain phosphorylation and the negative selection of B6.2.16 CD8 cells. Low -affinity binding of thymic self-peptides to B6.2.16 TCR resulted in the po sitive selection of B6.2.16 CD8 cells. Differences between the binding affi nities of self-peptides to B6.2.16 TCR accounted for the self-peptide speci ficity of B6.2.16 CD8 cell positive selection. We conclude that the relativ e affinity of TCR for thymic self-peptide/class I MHC is a critical paramet er in determining fate of CD8(+) cells during thymic selection.