Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN‐γ‐inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4⁺ T‐cell activation

Abstract

Malignant gliomas (MGs), lethal human central nervous system (CNS) neoplasms, contain tumor infiltrating lymphocytes (TIL). Although MHC class II molecules are frequently detected on MG cells, suggesting that they may be capable of antigen (Ag) presentation to CD4(+) T cells, deficiencies in CD4(+) T-cell activation are associated with these nonimmunogenic tumors. We evaluated regulation of the MHC class II transactivator (CIITA), the key intermediate that controls class II expression, in MG cells and tested whether MG cells could process native Ag. After interferon-gamma (IFN-gamma) stimulation, MG cells upregulated CIITA and class II molecules. IFN-gamma-inducible CIITA expression in MG cells, as well as primary human astrocytes, was directed by two CIITA promoters, pIV, the promoter for IFN-gamma-inducible CIITA expression in nonprofessional antigen-presenting cells (APC), and pIII, the promoter that directs constitutive CIITA expression in B cells. Both pIII and pIV directed CIITA transcription in vivo in MGs and ex vivo in IFN-gamma-activated primary MG cultures. We also demonstrate for the first time that MG cells can process native Ag for presentation to CD4(+) MHC class II-restricted Th1 cells, indicating that MG cells can serve as nonprofessional APC. CIITA may be a key target to modulate MHC class II expression, which could augment immunogenicity, Ag presentation, and CD4(+) T-cell activation in MG therapy.

Significance of the expression of major histocompatibility complex class II antigen, HLA‐DR and ‐DQ, with recurrence of papillary thyroid cancer

“…10 Both constitutive and IFNg-induced expression of MHC Class II antigen have also been described in other cancers, such as in melanoma cell lines and gliomas. 15,16 According to recent studies, CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC Class II antigen expression, and possibly through PKA and SRC kinase. 17 Epigenetic inactivation of MHC Class II genes and genomic instability may also be associated with the regulation of MHC Class II expression in tumor cells.…”

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

“…65 However, MHC class II is not expressed on the very few Langerhans cells that can occasionally be detected in human anagen hair bulbs by electromicroscopy or CD1a staining, which suggests that these are functionally impaired in this immunoprivileged region of the hair follicle. 7,18 Under pro-inflammatory conditions, namely after IFN-␥ stimulation, many skin cell types (including keratinocytes) can become non-professional antigen presenting cells via up-regulation of MHC class II.…”

Stat2-Dependent Regulation of MHC Class II Expression

“…Gene expression was normalized to a ␤-actin control. For RNase protection assay (RPA), 10 g of total macrophage RNA was denatured in formamide (30 l, 85°C, 5 min) and then hybridized with 10 5 cpm of labeled CIITA promoter-specific riboprobes (45-55°C; 16 h), as previously described (29,30). Samples were subsequently treated with RNase mixture (1.5 l, 40 min, 37°C; Ambion), 10 l of 20% SDS plus 2.5 l of proteinase K (15 min, 37°C), phenol extracted, ethanol precipitated, and fractionated by 8% urea-PAGE after heating samples in 5 l of loading buffer (Ambion; 3 min, 85°C).…”

“…generously provided by J. C. Patarroyo (University of California, San Francisco, CA) (30,32). pI (linearized with HindIII and transcribed with T7 polymerase) protects 335 nt (pI-specific bp 375-481 plus 228 bp of exon II).…”