Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3β loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
Human myelin oligodendrocyte glycoprotein is decorated with fucosylated N-glycans that are recognized by DC-SIGN+ DCs and microglia that control immune homeostasis.
Background: Endogenous functions of the recently identified membrane-associated RING-CH (MARCH) family of transmembrane ubiquitin ligases are undefined, except for MARCH-1.Results: MARCH-8 interacts with death receptor TRAIL receptor (R) R1, ubiquitinates TRAIL-R1, and down-regulates TRAIL-R1 from the cell surface at steady state.Conclusion: Steady-state cell surface levels of TRAIL-R1 are controlled by MARCH-8-mediated ubiquitination.Significance: TRAIL-R1 is the first identified substrate of endogenous MARCH-8.
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