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

记忆T淋巴细胞不断在体内循环以寻找同源抗原的范式最近被发现存在于多种组织（包括骨髓）中的记忆T细胞所挑战。然而，常驻记忆T细胞和循环记忆T细胞的分工和生活方式仍然是一个谜。我们已经获得了初步的证据，驻留在人类骨髓中的记忆T细胞既不循环也不激活。例如，尽管表达CD69，但增殖和整体基因表达分析将这些细胞定性为静止细胞。此外，在老年人的骨髓中发现了针对全身性儿童病毒抗原（如麻疹）的CD4+记忆T细胞，但在循环记忆T细胞中却没有发现。根据这些结果，我们假设骨髓记忆T细胞是常驻的，静止的，并保持对系统抗原的长期记忆。在提议的项目中，我们将测试和扩展这一假设。具体来说，我们将讨论记忆T细胞是如何在系统重新挑战时被划分、维持和重新激活的。这种方法将极大地促进我们对人类T细胞记忆的理解，这为疫苗和免疫疗法调节免疫提供了基本原理。

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.