Modulation of CD8+ T Cell Responses by HLA-F

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CD8+ T cells are critical for clearance of viral-infected cells and tumor cells. They recognize antigens presented by human leukocyte antigen class I (HLA-I) molecules. HLA-F is a non-classical HLA-I molecule that has recently been drawing a lot of attention due to its potential significance in several viral infections and cancers. Although HLA-F was previously believed to be expressed only as open conformers (without peptide), recent studies showed that HLA-F can also be expressed as peptide-associated form. Due to its limited polymorphisms, HLA-F is an attractive target for viral infection control and cancer immunotherapy. However, it is still not clear whether and how HLA-F modulates the function of CD8+ T cells. In this proposal, we expect to address the function of HLA-F in CD8+ T cell responses with the following specific aims: Aim 1: Determine the HLA-F antigen presentation pathway. Both of the accumulation in the endoplasmic reticulum (ER) and the open conformation on the cell surface indicate peptide loading of HLA-F in the ER is inefficient. Our preliminary study suggests an unconventional antigen presentation pathway. We will determine where and how peptides are loaded to HLA-F, which will facilitate the future vaccine design. Aim 2: Determine the effect of HLA-F on CD8+ T cell activation. HLA-F specific CD8+ T cells will be isolated from peripheral blood of pathogen-experienced donors. The isolated CTLs will be used to investigate how HLA-F presents peptides to CTL. Since HLA-F is predominantly expressed as open conformers, we will also determine the effect of HLA-F open conformers on CD8+ T cell activation. Successful completion of this proposal will reveal the antigen presentation mechanisms of HLA-F and how HLA-F modulates CD8+ T cell responses, contributing to developing HLA-F based immunotherapies.