UNPRIMED T-CELLS AM INEFFICIENTLY STIMULATED BY GLYCOSYLPHOSPHATIDYLINOSITOL-LINKED H-2K(B) BECAUSE OF ITS LIPID ANCHOR RATHER THAN DEFECTSIN CD8 BINDING

Many non-classical, or class Ib, MHC molecules, including those linked to the cell membrane via glycosylphosphatidylinositol (GPI) membrane anchors, are poor stimulators of primary cytotoxic T cell responses, S ome studies have suggested that certain amino acid substitutions in th e alpha 3 domains of class Ib molecules may adversely affect their abi lity to interact with CD8, thereby affecting their ability to stimulat e CD8(+) T cells, In this report we show that poor stimulation by GPI- linked class I MHC molecules is not simply due to a failure to interac t with CD8, but to a fundamental difference in the way T cells respond to GPI-anchored class I molecules, We have demonstrated this in two w ays, Firstly, we have shown that GPI-linked H-2K(b) molecules in which the amino acid sequence of the alpha 3 domain is identical to that of transmembrane H-2K(b) remain less effective stimulators of a primary T cell response than membrane-spanning H-2K(b) molecules, Secondly, us ing CD8(-) responder T cell hybridomas and responder T cells from tran sgenic mice expressing a CD8-independent TCR, we can show that the poo r stimulatory ability of GPI-linked H-2K(b) molecules is unrelated to their ability to interact with either CD8 or the TCR, These results su ggest that the transmembrane linkage of class I MHC molecules plays an important role in the initial priming of T cells.