Differential properties of peripheral versus central nervous system (CNS) antigen-presenting cells: relevance for antigen-presenting cell T cell interactions and implications for the pathogenesis and therapy of CNS inflammation

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Antigen presentation in the CNS is thought to play a critical role in the initiation and perpetuation of neuroinflammation. It is becoming apparent that microglial cells differ considerably from peripheral antigen-presenting cells in terms of their responses to inflammatory stimuli and their abilities to modulate immune responses. The proposed project aims at defining the relevant functional differences that exist between professional antigen-presenting cells in the periphery (monocytes, B cells, differentially matured dendritic cells) versus microglial cells with respect to their contributions to CNS inflammation. The project includes the investigation of how autologous and potentially autoreactive T cell activation is controlled or modulated by peripheral versus CNS antigenpresenting cells and how these findings might be relevant for the immunopathogenesis and the therapy of multiple sclerosis. Special consideration is given to how these differences might impact the steps of disease initiation, propagation and chronicity. Specifically, differences between the expression and regulation of the MHC class 11 antigen-processing machinery, novel members of the B7 family members of costimulatory molecules (B7-H2 (ICOS-L)/ICOS, B7-Hl (PD-L1)/PD-1non-PD-1, B7-DC (PD-L2)/PD1-non-PD1, B7-H3/X, B7-H4 (B7HSl)/BTLA-4), members of the immunoglobulin family and non-classical MHC molecules on distinct antigen-presenting cell subsets will be studied.