Visualizing interactions between XCR1+ dendritic cells and lymphocytes and deciphering their molecular regulation – XCR1DirectingCells

XCR1+ dendritic cells (DC) represent a minor population of immune cells in human and mouse. Yet they are strong activators of innate lymphoid cells (ILC) and CD8+ T cells, which effector responses allow efficient control of certain infections and cancer. With this project, we will explore a novel function of XCR1+ DCs: their orchestration of the micro-anatomical redistribution, and clustering of effector ILCs, including natural killer (NK) cells, and naïve and memory CD8+ T cells in the spleen. We will describe the migration pattern of XCR1+ DCs and of their cell partners within the different compartments of the spleen during primary viral, and secondary bacterial infections, by using light sheet fluorescent microscopy (LSFM). This innovative and cutting-edge technology allows deep imaging of rare populations in untouched organs. We will also decipher the molecular mechanisms regulating redistribution of XCR1+ DCs and of their cell partners (ILCs, plasmacytoid DCs, CD8+ and CD4+ T cells), and their interactions within the spleen. XCR1+ DCs selectively express the chemokine receptor XCR1, and rapidly secrete specific cytokines and chemokines upon infections in both mouse and human. We have generated and validated unique mouse models carrying selective inactivation of these factors in XCR1+ DCs. We will determine 1) to what extent these molecules are involved in the relocalization of immune cells by visualizing and quantifying regional distribution and cell-cell interactions in the entire lymphoid organ using LSFM; 2) how these interactions involving XCR1+ DCs promote efficient immune responses to infections; and 3) the molecules that regulate adhesion and motility of XCR1+ DCs. To the best of our knowledge, this will be the first time LSFM will be used to describe immune cell redistribution during infections in spleen.