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Project B2: Giorgi Tchitashvili, doctoral researcher (PhD)

LCMV as model for immune intervention by antigen targeting in chronic viral infections

Dendritic cells (DCs) are sentinels of the immune system and key players shaping the immune response. Many studies demonstrated that DCs could not only initiate immune responses against viruses or cancer cells, but are also important to maintain self-tolerance. Beside the secretion of cytokines and chemokines, DCs direct T cell immune responses by the presentation of peptides as MHC complexes. Cytosolic antigens, including viral antigens, are trimmed by the proteasome and presented as peptide:MHC I complex to CD8+ T cells, while exogenous antigens that are taken up by endocytosis are presented as peptide:MHC II complex to CD4+ T cells. However, the antigen processing machinery in DCs displays also the potential to present endocytosed proteins as peptide:MHC I complex (termed cross-presentation) and can present intracellular proteins as peptide:MHC II complex (a process dependent on autophagy). Different DC subsets have been described, namely plasmacytoid DCs (pDCs) as well as conventional DCs (cDCs). The latter can be classified as cDC1 or cDC2 displaying a unique functionality. However, it is not known yet, how the network of the different DCs subsets dictates the outcome of a protective or non-protective immune response. Within this project, we aim to study the hierarchy of the T cell responses induced by the DC subsets and want to dissect their role to induce protective immune responses. Therefore, we will use the well-known lymphocytic choriomeningitis virus (LCMV), namely the acute Armstrong and the persistent Clone 13 variants, as model infection in mice. We will deliver single or combinations of antigenic CD4 as well as CD8 peptides from the nucleo- as well as the glycoprotein of the virus to specific DC subsets. Therefore, we will utilize our antigen targeting strategy and deliver the antigens via DEC205 (to cDC1), DCIR2 (to cDC2), or FcγRIV (to cDC1 and cDC2 simultaneously). The vaccination efficacy will be studied, e.g. by restimulation assays and tetramer staining as well as in preventive and therapeutic LCMV infection models.