Mechanisms of CD4+ T Cell Exhaustion by Persistent Antigen and Chronic Inflammation

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Chronic infections like tuberculosis, malaria and HIV/AIDS are major challenges to global health. In such diseases, and in cancer, the immune system cannot clear the causing agent which then persists. Under such circumstances T cells become dysfunctional due to continued antigen presentation, inflammation, and debilitating microenvironments, a process summarily called exhaustion. In studies investigating CD4+ T helper cell exhaustion in a mouse model of regulatable antigen expression in vivo we have defined how the cells become exhausted by antigen presented at different doses and for different periods of time. Here we want to address how certain genes we have identified affect T helper cell exhaustion: A transcription factor (Helios), two pairs of paralog transcription factors (Tox and Tox2, Egr2 and 3) and a pair of MAP kinase inhibitors (Spry1 and 2) are likely to affect T helper cell exhaustion. Using mostly loxP flanked loci and an inducible Cre recombinase we will delete the genes specifically in the phase of exhaustion in cells exposed to different levels of persisting antigen. We expect the cells to exhibit a less exhausted phenotype. We will further analyse the target genes and chromatin changes affected by the deletions to find mechanisms of exhaustion that can be pharmaceutically interfered with to support immune responses to chronic infections and cancer. In addition we will investigate the role of acute and chronic inflammation for T cell exhaustion by three different kinds of infections with the LCM virus.