Regulation of LMP2 and TAP1 Genes by IRF-1 Explains the Paucity of CD8+ T Cells in IRF-1−/− Mice

Abstract

The TAP1 and LMP2 genes are central for class I MHC function and share a common promoter. Here, we analyze the molecular mechanism of IFN gamma up-regulation of TAP1 and LMP2. In vivo footprinting indicates IFN gamma up-regulates protein-DNA contacts at an IRF-E that is essential for the up-regulation of TAP1 and LMP2 by IFN gamma. Gel shift analysis indicates that this site binds IRF-1. The expression of TAP1 and LMP2 are both greatly reduced in IRF-1-deficient mice. Surface class I MHC as well as CD8+ T cells are reduced in IRF-1-/- mice. The role of IRF-1 in the regulation of TAP1 and LMP2 suggests a mechanism for the antiviral properties of IRF-1 and the unexpected deficiency of CD8+ T cells observed in IRF-1-/- mice.

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

“…The high basal levels of TAP1 and LMP2 mRNA in H929 is consistent with constitutive expression of IRF-1 and IRF-2, as both IRFs have been shown to contribute to regulation of the bidirectional promoter (41,42). This contrasts with the low levels of CIITA-pIV mRNA.…”

“…Following IFN-␥ treatment for 24 h, minimal induction of CIITApIV transcripts was detectable in H929 cells, compared with the substantial increase seen in HeLa cells. To demonstrate that H929 cells did not possess a global defect in the induction of IFN-␥ target genes, expression of TAP1 and LMP2, which are regulated from a shared IFN-␥ responsive bidirectional promoter, was examined (41). In contrast with CIITA-pIV, H929 constitutively express TAP1 and LMP2, and both genes are further induced in response to IFN-␥ treatment (Fig.…”

“…To address whether the difference in TAP1/ LMP2 and CIITA-pIV regulation was reflected in differential promoter occupancy, we performed ChIP analysis on chromatin prepared from untreated and IFN-␥-treated H929 cells. Samples were immunoprecipitated with control Ab, Ab to PRDM1, IRF-1, or IRF-2, and the fraction of precipitated input chromatin from the CIITA-pIV and the bidirectional TAP1/LMP2 promoter was assessed (41,43). The promoter of the cytokeratin-10 gene (KRT-10), which lacks an IRF-E sequence and is not expressed in lymphoid lineage cells was amplified as a negative control to assess nonspecific binding.…”

Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis

“…In addition, IRF-1 has several other antitumor activities, relevant in vivo. These are due to the immunomodulatory e ects of IRF-1, such as the stimulation of T-helper cells and NK cells (Duncan et al, 1996;Loho et al, 1997), transcriptional enhancement of MHC genes (Kirchho et al, 1993;Drew et al, 1995;Massa and Wu, 1995;Hobart et al, 1996) and of genes involved in antigen presentation (White et al, 1996;Chatterjee-Kishore et al, 1998). Thus, most events or drugs which enhance the expression or activity of IRF-1 might be useful in cancer therapy by inducing speci®c killing of transformed cells.…”

Co-occupancy of the interferon regulatory element of the class II transactivator (CIITA) Type IV promoter by interferon regulatory factors 1 and 2

“…Both IRF-1 and IRF-2, as well as other IRF family members, exert their transcriptional regulatory activity through binding to the highly conserved interferonresponse element (IRF-E) found in the promoters of various IFN-inducible genes, including the genes for IFN-a/b (Fujita et al, 1988;Taniguchi et al, 1997), 2'-5'-OAS (Benech et al, 1987), GBP (Lew et al, 1991;Briken et al, 1995), iNOS (Xie et al, 1993;Spink and Evans, 1997), MHC class I (Blanar et al, 1989;Chang et al, 1992), TAP1 Min et al, 1996;White et al, 1996), IL-4 (Li-Weber et al, 1994), IL-6 (Faggioli et al, 1997), and IL-7 (Aragane et al, 1997). The IRF-E is also found in the promoters of three constitutively expressed genes: EBNA1 (Schaefer et al, 1997), histone H4 (Vaughan et al, 1995(Vaughan et al, , 1998, and murine muscle VCAM-1 (Jesse et al, 1998), which are activated by IRF-2.…”