Investigating the immunomodulatory role of the Nonclassical MHC Molecule HLA-F in Human Pregnancy

/Abstract HLA-F is a nonclassical class I MHC (Ib) molecule that has been found expressed on a variety of cancers, shown to play a role in HIV and adenoviral infection, the neurological autoimmune disease ALS and, relevant to this application, is expressed throughout pregnancy. Despite the potential importance of this protein in these conditions, little is known about this molecule in terms of its function or even in which conformational state it is expressed. We have recently shown that, in addition to being expressed as a heavy chain only state, or open conformer (HLA-FOC), HLA-F can also be expressed as a bon fide peptide presenting molecule, associated with the β2m subunit (pHLA-F). Peptides are presented in an unconventional way, with the N- terminus not anchored within the groove and the potential for post-translational modifications featuring in peptide anchoring. Despite these advances, there remains much unknown about how these conformer states are regulated, how it engages its various receptors in each of these conformer states, and the role of HLA-F in reproduction. Thus, the aims of this proposal focus on addressing these questions and are: Aim 1: To identify which cell types express HLA- F during early and late gestation in normal, healthy pregnancies, and determine which extracellular conformer states and splice isoforms that HLA-F adopts on these cells. Using conformer-specific antibodies, we will determine what cell types express which (or both) forms. We will also pursue peptide elution studies from relevant cell lines to determine if the peptide differs from non-reproductive tissue. Aim 2: To identify and analyze the factors that regulate the production or interchange of HLA-F conformers and splice forms during gestation. We will explore the cellular factors that may play a role in switching HLA-F between peptide-loaded and HLA-FOC as well as an intriguing splice variant of HLA-F of unknown function. Finally, in Aim 3 we seek to establish the cellular and receptor repertoire that engage HLA-F in its various conformer states in human pregnancy and study the functional consequences of their engagement. Together these aims will provide an atlas of HLA-F expression, receptor engagement and provide insight into its role in human pregnancy. Project Number: 1U01AI173346-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Erin Adams | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $818,457 | Activity Code: U01 | Study Section: Molecular and Structural Immunology Study Section[MSI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U01AI17334601A1