Starke C, Frey S, Wellmann U, et?al. to the secondary lymphoid organs. Rather than pointing to artificial vs actual memory, the different observations of Pepper and colleagues and Tokoyoda and colleagues point to a selective recruitment of antigen\experienced CD4+ memory T cells to the bone marrow, dependent on yet poorly comprehended properties of the immune reaction.127 The selective recruitment to or survival in the bone marrow of memory T cells, reflecting real Esmolol immunological memories, is even more obvious in humans. We compared frequencies and numbers of CD4+ memory T Esmolol cells with specificity for unique vaccines and infectious pathogens, in blood and bone marrow of the same individuals, by identifying antigen\reactive T cells ex vivo.33 It turned out that in most adult human donors CD4+ memory T cells specific for viral pathogens encountered in child years, either by contamination or by vaccination, like measles, rubella, Esmolol and mumps, were managed exclusively in the bone marrow. Moreover, the very few cells detectable in blood showed a very limited scope of cytokine expression, while the cells of the bone marrow were polyfunctional, ie, they expressed several cytokines simultaneously. Memory CD4+ T cells realizing a persistent computer virus, namely cytomegalovirus, were present both in blood and bone marrow, while memory CD4+ T cells realizing pathogens of the skin, like Vaccinia and Candida, were more frequent in the blood than in the bone marrow. Such cells were presumably enriched in the skin,128, 129 although this has not been investigated in those donors. These differences in repertoire point to 1 potential sorting algorithm, namely archiving long\term remembrances for systemic pathogens in the bone marrow, in the form of reactive, polyfunctional CD4+ memory T cells. The unique maintenance of memory CD4+ T cells specific for child years vaccines/pathogens in the bone marrow Esmolol also implies Rabbit Polyclonal to NDUFB10 that those memory CD4+ T lymphocytes are not a part of a pool of circulating memory CD4+ T cells, but rather permanent residents of the bone marrow. 6.?THE LIFESTYLE OF BONE MARROW MEMORY T LYMPHOCYTES The presence of antigen\experienced T lymphocytes, both CD8+ and CD4+, in bone marrow has been known for quite Esmolol some time. Such cells had been considered to be managed by homeostatic proliferation or even cognate interactions with dendritic cells, as has been discussed before.110, 113, 130, 131, 132 Many of them express CD69 and some have upregulated expression of CD25. That is why they had been erroneously considered as proliferating cells in an activated state of memory.133 Recent evidence however suggests that resident memory T cells of the bone marrow are resting, not only in terms of proliferation (observe above) but also in terms of activation. Their transcriptomes are those of resting cells.33, 59, 81, 117 CD8+ memory T cells of the bone marrow express only about 0.6?pg of RNA per cell, as compared to activated CD8+ T cells, which express more than 10?pg of RNA per cell.117 Genes encoding cytokines or cytolytic enzymes and those promoting proliferation are not expressed at detectable levels. Genes that had been described as signature of tissue\resident memory T lymphocytes134 are expressed. Thus, at a global level of gene expression, memory T lymphocytes of the bone marrow are dormant, and unique from circulating memory T cells. This is confirmed, when we look not at gene expression itself, but rather at epigenetic imprinting of genes for reexpression.135 This analysis.