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

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.

Soos JM ，Krieger JI ，Stüve O ，King CL ，Patarroyo JC ，Aldape K ，Wosik K ，Slavin AJ ，Nelson PA ，Antel JP ，Zamvil SS ... -  《GLIA》

The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease.

Stüve O ，Youssef S ，Slavin AJ ，King CL ，Patarroyo JC ，Hirschberg DL ，Brickey WJ ，Soos JM ，Piskurich JF ，Chapman HA ，Zamvil SS ... -  《JOURNAL OF IMMUNOLOGY》

Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells.

Soos JM ，Morrow J ，Ashley TA ，Szente BE ，Bikoff EK ，Zamvil SS ... -  《JOURNAL OF IMMUNOLOGY》

Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-gamma.

Piskurich JF ，Gilbert CA ，Ashley BD ，Zhao M ，Chen H ，Wu J ，Bolick SC ，Wright KL ... -  《MOLECULAR IMMUNOLOGY》

Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-alpha.

During demyelinating disease of the central nervous system (CNS), locally elevated cytokine levels may induce upregulation of MHC class II molecules on otherwise low expressing or negative cell types such as microglia and astrocytes, since IFN-gamma has been shown to induce MHC class II expression on these cell types in vitro. While many transcription factors are involved with MHC class II expression, only the class II transactivator (CIITA) is tightly coordinated with IFN-gamma-inducibility. Control of CIITA gene expression is complex, involving four distinct promoters, two of which (promoters III and IV) are IFN-gamma-inducible in certain cell types. Here we demonstrate that IFN-gamma treatment of rat astrocytes induces only CIITA promoter IV activity in contrast to the murine macrophage cell line RAW 264.7 that uses both IFN-gamma-inducible promoters. In contrast to previously published reports, promoter IV activation is completely dependent upon an intact interferon regulatory factor-1 (IRF-1) but not STAT binding site using promoter constructs specifically mutated at these positions. Importantly, while TNF-alpha is able to synergize with IFN-gamma to increase astrocyte MHC class II expression in vitro, we show that treatment of rat astrocytes with TNF-alpha has no effect on CIITA promoter activity. These data demonstrate that TNF-alpha augments MHC class II expression through a mechanism downstream or independent of CIITA induction.

Nikcevich KM ，Piskurich JF ，Hellendall RP ，Wang Y ，Ting JP ... -  《JOURNAL OF NEUROIMMUNOLOGY》