Unprimed T cells are inefficiently stimulated by glycosylphosphatidylinositol-linked H-2Kb because of its lipid anchor rather than defects in 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. Some studies have suggested that certain amino acid substitutions in the alpha 3 domains of class Ib molecules may adversely affect their ability to interact with CD8, thereby affecting their ability to stimulate 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 interact 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 ways. Firstly, we have shown that GPI-linked H-2Kb molecules in which the amino acid sequence of the alpha 3 domain is identical to that of transmembrane H-2Kb remain less effective stimulators of a primary T cell response than membrane-spanning H-2Kb molecules. Secondly, using CD8- responder T cell hybridomas and responder T cells from transgenic mice expressing a CD8-independent TCR, we can show that the poor stimulatory ability of GPI-linked H-2Kb molecules is unrelated to their ability to interact with either CD8 or the TCR. These results suggest that the transmembrane linkage of class I MHC molecules plays an important role in the initial priming of T cells.
Zamoyska
R
R
Division of Molecular Immunology, National Institute for Medical Research, London, UK.
Ong
T
T
Kwan-Lim
G
G
Tomlinson
P
P
Robinson
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D016827:CD8 Antigens / Q000276:immunology*; D005786:Gene Expression Regulation; D017261:Glycosylphosphatidylinositols / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D006825:Hybridomas / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D016827:CD8 Antigens; D017261:Glycosylphosphatidylinositols; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D011948:Receptors, Antigen, T-Cell