Compartimentalization, maintenance and reactivation of human bone marrow resident and blood circulating memory T lymphocytes

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The paradigm that memory T lymphocytes are continuously circulating through the body in search of their cognate antigen has recently been challenged by the discovery of memory T cells residing in a variety of tissues, including the bone marrow. However, the division of labor and lifestyle of resident versus circulating memory T cells remain enigmatic. We have obtained initial evidence that memory T cells residing in the human bone marrow are neither circulating nor activated. For example, despite expressing CD69, proliferation and global gene expression analyses have characterized these cells as resting cells. In addition, CD4+ memory T cells specific for systemic viral childhood antigens, like measles, have been found in the bone marrow of elderly humans, but not among circulating memory T cells. From these results, we hypothesize that bone marrow memory T cells are resident, resting and maintain long-term memory to systemic antigens.In the proposed project, we will test and extend this hypothesis. Specifically, we will address how memory T cells are compartmentalized, maintained, and reactivated upon systemic re-challenges. This approach will significantly contribute to our understanding of human T cell memory, which provides the rationale for modulation of immunity by vaccines and immunotherapies.