The Class II transactivator, CIITA, controls the transcription of Major Histocompatibility Complex (MHC) genes. Since expression of MHC is required for immune recognition, CIITA acts as a master switch for the control of immune responses. Positive regulatory domain I-binding factor 1 (PRDI-BF 1), also known as B lymphocyte induced maturation protein-1 (BLIMP-1), is an important transcriptional repressor that triggers the terminal differentiation of B lymphocytes into plasma cells. PRDI-BF1 (BLIMP-l) suppresses the constitutive expression of CIITA both in normal plasma cells and in myeloma cells. The B cell malignancies, multiple myeloma and plasmacytoma, and also other types of tumors escape destruction by the immune system because they do not express CIITA. Although cytokines induce MHC class II expression in B lymphocytes and myeloma cells, the mechanisms for these effects are unknown. IL-4 and IFN-gamma, two important immunoregulatory cytokines with anti-tumor effects, induce CIITA expression in other cell types but few studies have examined CIITA induction in B cells. Since expression of the CIITA gene is regulated in a complex cell type specific manner, it is important to study the mechanisms controlling CIITA expression in all cell types relevant to disease. The goal of this project is to understand the mechanisms by which CIITA expression is induced and suppressed in B lymphocytes and myeloma cells.
Aim 1 examines induction of CIITA expression in these cells by IL-4 and IFN-gamma.
Aims 2 and 3 focus on mechanisms of CIITA suppression by PRDI-BF 1 (BLIMP-1).
Aim 2 investigates the role of this repressor in suppression of CIITA induction, while Aim 3 studies and compares the mechanisms by which constitutive and inducible CIITA expression are suppressed. Knowledge of the mechanisms by which cytokines control CIITA expression in B cells and by which CIITA is suppressed in multiple myeloma is key to uncovering pathways useful in the development therapies to induce MHC expression in neoplastic B cells for the recognition and destruction of these cells by the immune system. This knowledge is important to the development of therapies for other tumors as well.
|Zhao, Mojun; Flynt, Frederick L; Hong, Mei et al. (2007) MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Mol Immunol 44:2923-32|
|Chen, Han; Gilbert, Carolyn A; Hudson, John A et al. (2007) Positive regulatory domain I-binding factor 1 mediates repression of the MHC class II transactivator (CIITA) type IV promoter. Mol Immunol 44:1461-70|
|Piskurich, Janet F; Gilbert, Carolyn A; Ashley, Brittany D et al. (2006) Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-gamma. Mol Immunol 43:519-28|