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

Applicant Dr. Jun Dong
Subject Area Immunology
Term from 2017 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 389687267
 
Final Report Year 2022

Final Report Abstract

The primary observations that secondary immune reactions can be independent of circulating lymphocytes had been made 60 years ago. During the past two decades, significant populations of non-circulating, tissue-resident memory T lymphocytes (Trm) have been found in a variety of tissues, including the bone marrow. This has fundamentally challenged the paradigm that memory T cells (Tm) are continuously circulating through the body in search of their cognate antigens. However, the division of labor and lifestyle of Trm versus circulating Tm remain poorly understood. It is generally accepted that Trm protect their host tissues from secondary immune responses. We had originally described that, Tm from the human bone marrow are neither circulating nor activated, despite expressing CD69, and that CD4+ Tm specific for systemic viral childhood antigens, like measles, are found preferentially, if not exclusively, in the bone marrow of elderly humans, but not among circulating Tm. In this DFG project, we tested the hypothesis that human bone marrow Tm are resident, resting and maintain long-term memory to systemic antigens. We demonstrated for CD69+ murine CD8+ Tm, and CD69+ murine and human CD4+ Tm of the bone marrow, representing between 30%-60% of bone marrow Tm, that they express the signature transcripts of Trm. This suggests that a substantial proportion of bone marrow Tm are resident. We could also show that CD69+ CD4 Tm from the murine spleen express the murine Trm signature genes. Our findings propose a molecular mechanism of CD69+ Trm across tissues that is independent of anatomical locations. We established an approach for rapid and efficient isolation of Trm from the human skin. We could show that steady state human skin is enriched with CD69+ Trm that are resting, as the bone marrow Trm, but the skin Trm are specific for epithelial pathogens. We investigated the TCR CDR3 Vβ repertoires and the survival mechanism of bone marrow and blood Tm populations from the same individuals. We could show that CD69+ and CD69- Tm of the bone marrow and Tm of the blood are compartmentalized, and they are maintained by IL-7/15 via upregulating anti-apoptotic molecule BCL-2 and by stromal cells via downregulating the pro-apoptotic molecule NOXA. We demonstrated that Trm are mobilized into the blood within a day, and contribute to the systemic secondary immune reactions upon recall MMR vaccination of previously immune donors. We provided the evidence that Trm come from the bone marrow by their epigenetic "fingerprint” which discriminates Trm of the bone marrow from those of blood and spleen. In summary, results of this DFG project have provided the first evidence of the role for human Trm in systemic immunity. This project has shown that bone marrow Tm are resident, resting and maintain long-term memory to systemic antigens, and that bone marrow Trm can be rapidly mobilized and contribute to secondary systemic immune reactions. We have also defined the time window of the Trm mobilization and identified the epigenetic imprinting of spleen and bone marrow Trm.

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