How Chronic Antigen Presentation Compromises CD4+ T Cell Memory

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In chronic infections T cell reponses significantly differ from the ones to acute infections because antigen presentation and inflammation persist. T cells show a largely dysfunctional response to antigen and become "exhausted." Since there is a paucity of studies on the role and functionality of CD4+ T cells in chronic infections, we have developed a mouse model for the side-by-side generation of memory and exhausted CD4+ T cells by reversible tetracycline-regulated antigen presentation in vivo. This system is quantitatively tunable and targeted to dendritic cells without potentially complicating innate, B cell and CD8+ T cell responses. Preliminary experiments showed that antigenspecific CD4+ T cells become dysfunctional quickly and can recover only some of their functions upon antigen removal. In this project we will first investigate the phenotype of the exhausted cells in comparison to memory cells. We will assess how a chronically persisting virus (MCMV) or the repeated application of immunostimulatory RNA oligonucleotides as a substitute for a virally induced inflammation may affect the phenotype and functionality of the cells. Second, we will analyze signal transduction in the exhausted cells. Our preliminary data already suggested that calcium signaling, unlike the MAP kinase pathway, is operational in exhausted cells, indicating that they were not anergized in the classical sense. Third, we will identify molecules differing between memory and exhausted cells by mRNA and miRNA microarray analyses.