Nonclassical MHC-I presentation as a sensor of ER stress 4569

Abstract Description ER aminopeptidases (ERAPs) trim peptides to curate the repertoire available for MHC-I presentation and subsequent T cell immunosurveillance. In mice, loss of ERAP leads to presentation of an immunodominant peptide on nonclassical Qa-1b. This epitope, termed ‘QFL’, is recognized by an unconventional CD8 T cell with memory-like phenotype targeting cells with defective antigen processing. However, it is unknown whether QFL presentation occurs in response to other cellular stressors, or whether human nonclassical HLA-E serves a similar function. Genetic knockout or small molecule inhibition of ERAP activity in cells led to presentation of the QFL epitope as detected by a QFL-specific hybridoma reporter. We investigated other pharmacologic modulators of cellular homeostasis, including ER stress and autophagy. Our initial findings show that ER stress responses can lead to presentation of the QFL epitope. We propose that these unconventional T cells may sense ER stress or other disruptions of cellular homeostasis that intersect pathways of altered antigen processing. Furthermore, we show that expression of either human ERAP1 or ERAP2 suppressed QFL presentation, demonstrating redundancy of human ERAPs in nonclassical MHC-I presentation which will benefit detection of potential HLA-E epitope homologs. In this way, nonclassical MHC-I presentation could serve as a marker of intracellular stress sensed by T cells, with relevance to immune surveillance of cancer and autoimmune disease. Funding Sources Supported by NIH R01AI130210; NIH R37AI060040; NIH R01AI149341; JHMI supplemental funding to J. David Peske Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)