Endo-lysosomal assembly variations among Human Leukocyte Antigen class I (HLA-I) allotypes
- University of Michigan-Ann Arbor, United States
Abstract
The extreme polymorphisms of HLA-I proteins enable the presentation of diverse peptides to cytotoxic T lymphocytes (CTL). The canonical endoplasmic reticulum (ER) HLA-I assembly pathway enables presentation of cytosolic peptides, but effective intracellular surveillance requires multi-compartmental antigen sampling. Endo-lysosomes are generally sites of HLA class II assembly, but human monocytes and monocyte-derived dendritic cells (moDCs) also contain significant reserves of endo-lysosomal HLA-I molecules. We hypothesized variable influences of HLA-I polymorphisms upon outcomes of endo-lysosomal trafficking, as the stabilities and peptide occupancies of cell surface HLA-I are variable. Consistent with this model, when the endo-lysosomal pH of moDCs is disrupted, HLA-B allotypes display varying propensities for reductions in surface expression, with HLA-B*08:01 or HLA-B*35:01 being among the most resistant or sensitive respectively, among eight tested HLA-B allotypes. Perturbations of moDC endo-lysosomal pH result in redistribution of HLA-B*35:01, but not HLA-B*08:01, to LAMP1+ compartments and increase HLA-B*35:01 peptide receptivity. These findings reveal the intersection of the vacuolar cross-presentation pathway with a constitutive assembly pathway for some HLA-B allotypes. Notably, cross-presentation of epitopes derived from two soluble antigens was also more efficient for B*35:01 compared to B*08:01, even when matched for T cell response sensitivity, and more affected by cathepsin inhibition. Thus, HLA-I polymorphisms dictate the degree of endo-lysosomal assembly, which can supplement ER assembly for constitutive HLA-I expression and increase the efficiency of cross-presentation.
Data availability
The original data have been deposited to Dryad. Source data for figures have also been provided.
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Endo-lysosomal assembly variations among Human Leukocyte Antigen class I (HLA-I) allotypesDryad Digital Repository, doi:10.5061/dryad.qbzkh18nb.
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HLA-I peptidomespublic proteomics repository MassIVE; MSV000084172/.
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HLA-I peptidomespublic proteomics repository MassIVE; MSV000080527.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (RO1AI044115)
- Malini Raghavan
National Institute of Allergy and Infectious Diseases (R21AI64025)
- Malini Raghavan
National Institute of General Medical Sciences (T32GM008353)
- Eli Olson
National Institute of Allergy and Infectious Diseases (T32AI007413)
- Eli Olson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Informed consent from healthy donors for blood collections and HLA genotyping was procured in accordance with a University of Michigan IRB approved protocol (HUM00071750). The consent document included information that results of the studies could be published in an article without identifying information about blood donors. Donors were genotyped at the HLA locus as previously described (Yarzabek et al., 2018). Alternatively, non-genotyped donor blood was obtained from the University of Michigan Platelet Pharmacology and Physiology core in accordance with a University of Michigan IRB approved protocol (HUM00107120).
Copyright
© 2023, Olson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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