Major Histocompatibility Complex (MHC) class II, plays a major role in immune recognition. They present antigens to CD4 T cells in the periphery to mount an immune response and the expression of MHC in the thymus is essential for CD4 T cell development. The proper expression of MHC class II molecules is crucial to regulate immune responses. The aberrant expression of MHC class II may influence the triggering and pathogenesis of autoimmunity and the lack of MHC class II expression can cause immunodeficiency. Therefore, it is import to understand the mechanism of MHC gene regulation to modulate the immune response. The long-term goal of this proposal is to have a better understanding of the MHC class II gene regulation, and ultimately the role of MHC class II molecules in immune system. To achieve this goal we will focus on the MHC class II trans-activator (CIITA), a transcriptional factor required for the transcription of MHC class II genes. We and others have shown that CIITA is essential for both constitutive and IFN-gamma inducible expression of MHC class II genes in vitro. In addition, CIITA regulates multiple genes involved in antigen presentation such as invariant chain and H-2M genes, and the introduction of CIITA is sufficient to activated these genes. The critical role of CIITA was further confirmed in vivo using CIITA deficient mice generated by us. However, the regulation of CIITA gene is poorly understood even though the significance of CIITA is greatly appreciated. We believe that the study of CIITA gene regulation is essential because CIITA expression is directly linked to the MHC class II gene transcription. Therefore, we propose to study following aims to achieve our goal: (1) study the regulation of the constitutive and IFN-gamma inducible expression of the CIITA gene to define elements mediating CIITA gene transcription. (2) study the inactivation of CIITA gene expression in mouse T cells. This is based on our previous observation that mouse T cells are unable to express MHC class II due to the lack of CIITA transcription. (3) study the CIITA independent regulation of MHC class II genes. We showed that CIITA deficient mice do not express MHC class II on antigen presenting cells. However, a subset of thymic epithelial cells of CIITA deficient mice express MHC class II suggesting that there is an alternate regulatory mechanism for MHC class II transcription. Our studies will define the essential and non- redundant pathways of MHC class II regulation and the information generated form this proposal will help to modulate the level if MHC class II by either manipulating CIITA or signals mediating the induction of MHC class II gene transcription. The findings should lead to clinical application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI041510-03
Application #
2887481
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Kerr, Lawrence D
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Sisk, Tyler J; Nickerson, Kevin; Kwok, Roland P S et al. (2003) Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int Immunol 15:1195-205
Chang, Cheong-Hee; Gourley, Tania S; Sisk, Tyler J (2002) Function and regulation of class II transactivator in the immune system. Immunol Res 25:131-42
Gourley, Tania S; Patel, Dipak R; Nickerson, Kevin et al. (2002) Aberrant expression of Fas ligand in mice deficient for the MHC class II transactivator. J Immunol 168:4414-9
Gourley, T S; Chang, C H (2001) Cutting edge: the class II transactivator prevents activation-induced cell death by inhibiting Fas ligand gene expression. J Immunol 166:2917-21
Nickerson, K; Sisk, T J; Inohara, N et al. (2001) Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J Biol Chem 276:19089-93
Sisk, T J; Roys, S; Chang, C H (2001) Self-association of CIITA and its transactivation potential. Mol Cell Biol 21:4919-28
Sisk, T J; Gourley, T; Roys, S et al. (2000) MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300. J Immunol 165:2511-7