It is not clear why the N-terminal autoantigenic determinant of myelin basic protein (MBP), Ac1-9, is dominant in the B1O.PL (H-2 u ) mouse, given its weak I-A u -MHC binding affinity. Similarly, how do high-affinity T cells specific for this determinant avoid negative selection? Because the MBP:1-9 sequence is embryonically expressed uniquely in the context of Golli-MBP, determinants were sought within the contiguous N-terminal ''Golli'' region that could out-compete MBP:1-9 for MHC binding, and thereby prevent negative selection of the public response to Ac1-9, shown here to be comprised of a V8.2J2.7 and a V8.2J2.4 expansion. Specifically, we demonstrate that Ac1-9 itself can be an effective inducer of central tolerance induction; however, in the context of Golli-MBP, Ac1-9 is flanked by determinants which prevent its display to autoreactive T cells. Our data support competitive capture as a means of protecting high-affinity, autoreactive T cells from central tolerance induction.
CD1 proteins are unique in their ability to present lipid Ags to T cells. Human CD1b shares significant amino acid homology with mouse CD1d1, which contains an unusual putative Ag-binding groove formed by two large hydrophobic pockets, A′ and F′. We investigated the function of the amino acid residues that line the A′ and F′ pockets of CD1b by engineering 36 alanine-substitution mutants and analyzing their ability to present mycobacterial glycolipid Ags. Two lipid Ags presented by CD1b were studied, a naturally occurring glucose monomycolate (GMM) isolated from mycobacteria, which contains two long alkyl chains (C54-C62 and C22-C24) and synthetic GMM (sGMM), which includes two short alkyl chains (C18 and C14). We identified eight residues in both the A′ and F′ pockets that were involved in the presentation of both GMM and sGMM to T cells. Interestingly, four additional residues located in the distal portion of the A′ pocket were required for the optimal presentation of GMM, but not sGMM. Conversely, nine residues located between the center of the groove and the F′ pocket were necessary for the optimal presentation of sGMM, but not GMM. These data indicate that both the A′ and F′ pockets of human CD1b are required for the presentation of lipid Ags to T cells.
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