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-Dependent Control of the MHC Class I Antigen-Processing and Peptide-Loading Pathway1
* Section of Experimental Haematology, Leeds Institute of Molecular Medicine, and
Academic Unit of Oncology and Haematology, Haematological Malignancy Diagnostic Service, University of Leeds, Leeds, United Kingdom
A diverse spectrum of unique peptide-MHC class I complexes guides CD8 T cell responses toward viral or stress-induced Ags. Multiple components are required to process Ag and facilitate peptide loading in the endoplasmic reticulum. IFN-
, a potent proinflammatory cytokine, markedly up-regulates transcription of genes involved in MHC class I assembly. Physiological mechanisms which counteract this response are poorly defined. We demonstrate that promoters of functionally linked genes on this pathway contain conserved regulatory elements that allow antagonistic regulation by IFN- and the transcription factor B lymphocyte-induced maturation protein-1 (also known as PR domain-containing 1, with ZNF domain (PRDM1)). Repression of ERAP1, TAPASIN, MECL1, and LMP7 by PRDM1 results in failure to up-regulate surface MHC class I in response to IFN- in human cell lines. Using the sea urchin prdm1 ortholog, we demonstrate that the capacity of PRDM1 to repress the IFN response of such promoters is evolutionarily ancient and that dependence on the precise IFN regulatory factor element sequence is highly conserved. This indicates that the functional interaction between PRDM1 and IFN-regulated pathways antedates the evolution of the adaptive immune system and the MHC, and identifies a unique role for PRDM1 as a key regulator of Ag presentation by MHC class I.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Medical Research Council Clinician Scientist Fellowship (to R.M.T).
2 Address correspondence and reprint requests to Dr. Reuben M. Tooze, Section of Experimental Haematology, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, U.K. E-mail address: r.tooze{at}leeds.ac.uk
3 Abbreviations used in this paper: LMP, large multifunctional peptidase; MECL-1, multicatalytic endopeptidase complex subunit-1; ER, endoplasmic reticulum; ERAP1, ER amino peptidase-1; BLIMP-1, B lymphocyte-induced maturation protein-1; PRDM1, PR domain-containing 1, with ZNF domain; IRF, IFN regulatory factor; IRF-E, IRF element; ChIP, chromatin immunoprecipitation; EGFP, enhanced GFP; siRNA, short interfering RNA.
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