B Lymphocyte-Induced Maturation Protein-1/Positive Regulatory Domain I-Binding Factor 1 regulates two amino peptidases associated with antigen processing (78.9)

Abstract

Abstract A diverse repertoire of specifically-trimmed peptides is presented by the Major Histocompatibility Complex Class I (MHCI) pathway of antigen presentation for immune surveillance by CD8+ cytotoxic T cells. These peptides are generated in the cytosol, then trimmed by amino peptidases to meet the binding requirements of MHCI. Two endoplasmic reticulum amino peptidases, ERAP1 and ERAP2, perform this function in human cells. Positive Regulatory Domain I-Binding Factor 1 (PRDI-BF1) called B Lymphocyte Induced Maturation Protein-1 (BLIMP-1) in mice drives the differentiation of B lymphocytes into plasma cells. We demonstrated that PRDI-BF1/BLIMP-1 regulates the MHCII pathway of antigen presentation by repressing MHC class II transactivator (CIITA) transcription. We now show that PRDI-BF1/BLIMP-1 plays a key role in modulating the MHCI pathway. Functional promoter analyses and protein/DNA binding studies demonstrate that both full-length PRDI-BF1/BLIMP-1 and a truncated form of this transcription factor called PRDI-BF1β, expressed in myeloma cells and associated with resistance to chemotherapy in diffuse large B-cell and T-cell lymphoma, mediate repression of ERAP1 and ERAP2. Repression occurs through a site nearly identical in sequence to a site for repression of CIITA. IFN-γ or ectopic expression of IRF-1 up regulates ERAP expression even in PRDI-BF1/BLIMP-1-expressing cells. The goal of this work is to uncover pathways useful in therapeutic approaches to improve the ability of the immune system to recognize and destroy PRDI-BF1-expressing tumors. Supported by grants from the National Cancer Institute (RO1CA102203) and MEDCEN Community Health Foundation of Central Georgia.