Memories that last: Dynamics of memory cells in mice, dirty mice, and men

Abstract

One of the major qualities of the immune system is its ability to remember a pathogen for when it is encountered again in the future. We can think of immunological memory as a library filled with books (cells) that remember specific pathogens or diseases. The comparison of immunological memory to a library leads to two important questions. First, are immunological memory cells maintained as statically as books: are memory cells that were created decades ago the same ones we find back today, or are they maintained more dynamically? Second, where is the library? At any given moment, only an estimated 2% of lymphocytes are in the peripheral blood, but the majority of human lymphocytes reside in lymphoid organs such as the lymph nodes, spleen, thymus, and bone marrow (BM). In this thesis, we have studied the lifespan of immune memory cells in various organs using heavy water labeling in mice and men. Specifically, we have used “dirty mice”, which due to their more natural microbiome are thought to resemble the human situation better and form a translational bridge between animal research and clinical application. We have shown that most immune cells are much shorter lived than the immunological memory they convey. For memory T cells, the lifespan depended slightly on their location: memory T cells in peripheral blood, liver, lung, and skin have a comparable lifespan, but memory T cells in bone marrow are markedly longer-lived. This thesis also questions the concept of long-lived plasma cells, showing in both mice and men that most plasma cells are relatively quickly replaced after generation. In this sense, immune cells are much different than truly long-lived cells, such as neurons, that can live as long as their host. These insights show that the immune system is not a static system that merely stores memories, but is dynamic and adaptable and constantly prepared for the challenges of an ever-changing world around us.