Renal parenchymal cells, tubular epithelial cells (TEC) and/or antigen presenting cells (APC) interact with kidney infiltrating T cells and provide signals that drive, or halt T cell activation. The MRL-Faslpr model is appealing to dissect intrarenal signals that regulate lupus nephritis, and the systemic illness, since it shares features with human lupus. The CD28/CTLA4-B7 family of molecules provides positive and negative signals that regulate T cell activation. There are two newly identified members; 1) the inducible costimulator (ICOS), and its ligand ICOS-L that imparts positive and negative signals that regulate T cell activation, and 2) programmed death-1 (PD-1), and its ligands PD-L1 and PD-L2, that solely deliver negative signals that terminate immune responses. We hypothesize that the ICOS and PD-1 T cell pathways regulate immune responses and disease initiation/progression in lupus nephritis. The overall goal is to dissect the functions of these pathways, and investigate the mechanisms by which renal parenchymal cells, and APC regulate lupus nephritis.
The specific aims are: 1) To determine the temporal expression, magnitude, and localization of the iCOS/ICOS-L and PD-1/PD-L1 molecules during lupus nephritis, and the systemic illness in mice. We will correlate ICOS and PD-1 expression patterns with MRL-Faslpr renal pathology and the systemic illness; determine their regulation on TEC; and compare the intrarenal ICOS and PD-1 pathway expression in several mouse strains with lupus nephritis. 2) To establish whether blocking the ICOS pathway regulates lupus nephritis in MRL (+/- Faslpr) mice. We will determine whether deleting ICOS, and blocking ICOS and ICOS-L in MRL mice alters the tempo and severity of lupus nephritis and the systemic illness; and establishes whether ICOS-L on TEC regulates T cell activation. 3) To establish whether blocking the PD-1 pathway regulates lupus nephritis in MRL mice. We will test the hypothesis that the PD-1 pathway provides a negative regulatory signal to block intrarenal T cell activation. We will determine whether deleting PD-L1, and blocking PD-1/PD-LI/PD-L2 during lupus nephritis in MRL mice, worsens disease. We will determine whether B7-1/B7-2 T cell activation signals over-ride the PD-1 pathway inhibitory signals; establish whether altered nephritis in PD-L1 deficient MRL mice is a result of deleting PD-L1 on leukocytes and/or on renal parenchymal cells; and determine whether TEC expressing PD-L1 inhibit T cell activation. Our ultimate goal is to determine whether ICOS and PD-1 pathways are potential therapeutic targets for lupus nephritis.
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