The MHC-Ib Molecule HLA-F Presents Peptides and Regulates Immunity Through Interactions with NK-Cell Receptors /

Saved in:
Bibliographic Details
Author / Creator:Dulberger, Charles Lefco, author.
Ann Arbor : ProQuest Dissertations & Theses, 2017
Description:1 electronic resource (111 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
URL for this record:
Hidden Bibliographic Details
Other authors / contributors:University of Chicago. degree granting institution.
Notes:Includes supplementary digital materials.
Advisors: Erin J. Adams Committee members: Sean Crosson; Bana Jabri; Vincent J. Lynch.
Dissertation Abstracts International, Volume: 78-12(E), Section: B.
Summary:Evidence is mounting that HLA-F regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK-cell receptors (NKRs). We present structural, biochemical and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation in the antigen-binding cleft (R62W) that has produced an open-ended groove that accommodates particularly long peptides. Compared to empty HLA-F open conformers (OC), HLA-F tetramers bound with human-derived peptides differentially stain leukocytes suggesting peptide-dependent engagement. Our binding studies and functional assays confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F OC. The complex structure of peptide-loaded β 2m-HLA-F bound to the inhibitory LIR1 reveals similarities to high-affinity UL18 recognition and a docking strategy that relies on contacts with the HLA-F heavy chain as well as β2m, precluding binding to HLA-F OC. These findings provide the biochemical framework for how HLA-F regulates immunity via interactions with NKRs. Supplementary Table 2.2, which contains the peptide sequences eluted from HLA-F produced in HEK293T cells, can be found online.