Epigenetic mechanisms that maintain immunological memory in CD4 T cells

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We are using T cells as a model to investigate how long-term immunity is maintained for many years in the absence of the infection that initiated the response. Infections trigger the immune system to activate naive T cells to mount an immune response. Once a cycle of infection is over, a small population of long-living memory T cells still remain which retain a memory of previous infections and allow a faster response the second time around. Memory cells underpin the basis of vaccination, and provide the immune system with the capacity to rapidly respond when re-challenged with the same infection. We recently published studies using an in vitro model to demonstrate that the initial activation of naive T cells leads to permanent alterations in the chromatin structure of their chromosomes. We found that ~3000 sites within chromosomes are converted to islands of active chromatin near genes that respond rapidly to activation in memory T cells but not in naive T cells which have never been activated before. This reprogramming leaves hundreds of genes "ready to go" and able to respond immediately when inducible factors are once again turned on by active T cell receptors (TCRs). In the course of these studies we found that an inducible transcription factor that directs the activation inducible genes (AP-1) has to cooperate with two other factors (ETS-1 and RUNX1) for the initial activation, and after the activating agent had gone away ETS-1 and RUNX1 remain stably bound. Based on this data, we established a hit-and-run model of the establishment of immunological memory whereby AP-1 is required to open up new regions of chromatin around inducible genes, but that once formed, continuous binding of AP-1 is not required for the maintenance of primed genes by ETS-1 and RUNX1.We know very little about how previously activated T cells are able to retain this memory for many years. This proposal will use normal and genetically modified mice as models to address this question. We already have hints of what molecules may be involved. The maintenance of memory does not require continued activation of those proteins that bind antigens (TCRs). However, previous studies in mice and humans showed that other types of receptors (IL-7R) and OX40) are essential to mount a secondary response by memory T cells. Based on our previous findings, we hypothesize that the long-term maintenance of T cell memory is supported via transient activation of AP-1 by IL 7R and OX40 when memory cells passage through lymph nodes as they migrate about the body, which, in turn, ensures that RUNX1 and ETS-1 remain bound. This continuous reinforcement of epigenetic priming may help explain why memory T cells can persist for many years after an infection.The information gained from this proposal will help to explain how immunological memory is retained. It will also shed light on abnormal instances of immune activation that are detrimental for the organism as in case of autoimmune diseases. This knowledge is essential if we want to influence immunological memory in a diseased cellular environment. Our basic studies will pave the way for further, more focused approaches to address this issue.