Quantitative predictions of peptide binding to MHC class I molecules using specificity matrices and anchor-stratified calibrations.

Peptides are key immune targets. They are generated by fragmentation of antigenic proteins, selected by major histocompatibility complex (MHC) molecules and subsequently presented to T cells. One of the most selective requirements is that of peptide binding to MHC. Accurate descriptions and predictions of peptide-MHC interactions are therefore important. Quantitative matrices representing MHC class I specificity can be used to search any query protein for the presence of MHC binding peptides. Assuming that each peptide residue contributes to binding in an additive and sequence independent manner, such "crude" matrix-driven predictions can be expressed as a quantitative estimates of binding strength. Crude matrix-driven predictions are reasonably uniform (i.e. precise), however, there is a general tendency towards overestimating binding (i.e. being inaccurate). To evaluate and possibly improve predictions, we have measured the MHC class I binding of a large number of peptides. In an attempt to further improve predictions and to include sequence dependency, we subdivided the panel of peptides according to whether the peptides had zero, one or two primary anchor residues. This allowed us to define unique anchor-stratified calibrations, which led to predictions of improved precision and accuracy.

Interleukin 15 is a growth factor for human thymocytes with preferential effect on CD8(+)cells.

The effects of IL-15, as compared to IL-2, on growth of human thymocytes has been evaluated. Expression of comparable amounts of receptor chains was found on IL-2 and IL-15 cultured thymocytes, as well as comparable receptor signalling. However, IL-15 was superior to IL-2 in promoting CD8(+)thymocyte growth, whereas CD4(+)cells proliferated to a higher extent in IL-2 cultures. CD4(+)8(+)and CD4(-)8(-)thymocytes expanded equally well in both culture types.

Superantigens are presented by and activate thymocytes from infants.

A high percentage of human fetal and postnatal thymocytes express MHC class II molecules. This raises the possibility that human thymocytes in early life are able to present peptides to other immature T cells and thereby initiate thymic selection of these cells. Here we address this question by exposing newly harvested infant thymocytes to superantigen (Sag) which binds to the T-cell receptor and to MHC class II chains outside the peptide binding groove. The results show that the thymocytes are able to present Sag and to be activated to proliferation as well as apoptosis by Sag presented by other thymocytes. The absence of responses to Sag with mutations in class II binding sites showed that class II molecules were necessary for the responses, and very low expression of class II molecules on CD4-8- cells indicates that the demonstrated T-cell/T-cell interactions are confined to T-cell receptor-positive CD4+8+, CD4+8-, and CD4-8+ cells. These latter subsets were shown to be able to present Sag to each other. These findings suggest that class II+ thymocytes may participate in the selection of self-restricted T cells during a critical period in the shaping of the human immune system.