Key Points• Matching for MICA significantly reduces the incidence of acute and chronic GVHD in otherwise HLA 10/ 10-matched unrelated-donor HCT.• Our results formally define MICA as a novel major histocompatibility complex-encoded human transplantation antigen.

CD1e is the only human CD1 protein existing in soluble form in the late endosomes of dendritic cells, where it facilitates the processing of glycolipid antigens that are ultimately recognized by CD1b-restricted T cells. The precise function of CD1e remains undefined, thus impeding efforts to predict the participation of this protein in the presentation of other antigens. To gain insight into its function, we determined the crystal structure of recombinant CD1e expressed in human cells at 2.90-Å resolution. The structure revealed a groove less intricate than in other CD1 proteins, with a significantly wider portal characterized by a 2 Å-larger spacing between the α1 and α2 helices. No electron density corresponding to endogenous ligands was detected within the groove, despite the presence of ligands unequivocally established by native mass spectrometry in recombinant CD1e. Our structural data indicate that the water-exposed CD1e groove could ensure the establishment of loose contacts with lipids. In agreement with this possibility, lipid association and dissociation processes were found to be considerably faster with CD1e than with CD1b. Moreover, CD1e was found to mediate in vitro the transfer of lipids to CD1b and the displacement of lipids from stable CD1b-antigen complexes. Altogether, these data support that CD1e could have evolved to mediate lipidexchange/editing processes with CD1b and point to a pathway whereby the repertoire of lipid antigens presented by human dendritic cells might be expanded.3D structure | glycolipid antigen presentation | human CD1b | lipid antigen editing | lipid transfer protein F our transmembrane CD1 molecules (CD1a, are expressed in different cell-specific combinations by human immune cells and, among these, in dendritic cells (DCs), the professional antigen-presenting cells (APCs). These proteins present self or microbial lipid antigens to T cells, thus participating in innate and adaptive immunity (1, 2). Myeloid DCs also express a fifth isoform, CD1e, which indirectly participates in glycolipid antigen presentation. This protein has been found to facilitate the processing of complex mycobacterial hexamannosylated phosphatidylinositol (PIM 6 ) by lysosomal α-mannosidase into dimannosylated forms (PIM 2 ) that activate CD1b-restricted T-cell clones (3).In several respects, CD1e behaves differently from the other human CD1 family members. After biosynthesis, all membraneanchored CD1 molecules reach the Golgi compartments. Apart from CD1d, which is also delivered directly to endosomes (4), CD1a-d molecules are then transported to the plasma membrane, where they have been shown to bind some antigens. Subsequently, CD1 molecules are constitutively internalized into the endocytic network, where they capture antigenic ligands (4). Finally, the CD1-antigen complexes cycle back to the plasma membrane to activate specific T lymphocytes. In contrast, CD1e remains exclusively intracellular. After reaching the Golgi compartments, CD1e is addressed to sorting endosomes and from there to CD1...

Background: To become antigenic, mycobacterial hexamannosylated phosphatidyl-myo-inositol (PIM 6 ) undergo CD1e-assisted ␣-mannosidase processing. Results: Measuring membrane-to-membrane PIM transfer, CD1e selectively transferred diacylated PIM species in accordance with the fact that liposome-inserted di-acylated PIM 6 were the only PIM species digested into antigenic molecules by ␣-mannosidase. Conclusion: CD1e assists PIM processing through its lipid transfer protein property. Significance: This study reveals the molecular mechanisms by which CD1e contributes to lipid immunoediting.