MHC class II regulation is central in importance for understanding antigen (Ag) presentation and CD4 +T cell activation in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Interferon-gamma (IFNgamma), a pleiotropic cytokine, is considered a requirement for class U induction on nonprofessional Ag presenting cells (APC), including resident CNS APC. Yet, IFNgamma-deficient mice are susceptible to EAE. The MHC class II transactivator (CIITA) is a key intermediate in IFNgamma-inducible and constitutive class II expression. CIITA-deficient mice are resistant to EAE, indicating that CIITA-dependent class II expression by resident CNS APC is required for CNS inflammation. The in vivo role of CIITA in class II expression by microglia, a potent CNS APC, is not known. CIITA also directs expression of invariant chain (Ii) and HLA-DM, molecules involved in endocytic Ag processing. Studies of Ii and H-2M deficient mice and mice that selectively express Ii p31 and p41 suggest that Ag processing by CNS APC is required for initial CNS Ag presentation, although this possibility has not been tested directly. Ii p41 may stabilize certain peptides, providing advantage in Ag presentation. Ii p31, p41 and wild-type mice are similarly susceptible to acute EAE, but Ii p41 mice have a more severe course, suggesting that Ii p41 may influence Ag presentation in chronic EAE. The principle goals of this research program are to investigate the role of CIITA and gammaIFN class II expression and the role of Ag processing in EAE. We propose to examine the role of CIITA in IFNgamma-dependent and IFN(-independent class II expression by CNS APC. We hypothesize that constitutive CIITA-directed class II by microglia and macrophages in vivo will promote Ag presentation and EAE development, and that when CIITA-directed class II expression is restricted to macrophages and microglia, Ag presentation by these APC alone will be sufficient for initial T cell activation in EAE. We hypothesize that Ag processing is required for initial CNS Ag presentation and that the particular Ii isoform may alter Ag presentation during chronic EAE.
The Specific Aims are to: (1) evaluate the role of IFNgamma and IRF-1 on CIITA regulation on class II expression by CNS APC, (2) examine how constitutive CIITA directed class II expression by microglia and macrophages influences susceptibility to CNS inflammation, (3) determine the role of Ag processing in CNS Ag presentation in EAE through use of bone marrow chimera mice constructed from Ii and H-2M deficient mice, and (4) to evaluate how the Ii isoform influences chronic EAE severity through analysis of mice that selectively express Ii p31 or p41. These studies will provide valuable information regarding CNS class II regulation, which may provide insight for development of therapeutic means to modulate class II expression and T cell activation in MS.
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