Trends in Immunology
The bone marrow: a nest for migratory memory T cells
Introduction
Fully functional mature T lymphocytes inhabit the bone marrow, which is demonstrated by the ability of whole bone marrow to cause graft versus host disease when transplanted into allogeneic hosts. Recently, T cells in the bone marrow have attracted renewed interest because T cells reactive against autologous pre-malignant cells and cancer cells are found preferentially in the bone marrow of non-immunised patients, possibly participating in the local control of tumour development and metastasis growth 1, 2. Substantial migration of blood CD4 cells to vertebral and iliac marrow has been documented in normal human subjects [3]. Nevertheless, the bone marrow has often not been included in the schemes of T-lymphocyte traffic (e.g. Refs 4, 5, 6). Here, we will review neglected findings and recently published observations regarding bone marrow T cells in different species, focussing on their involvement in antigen-specific responses and the migratory pathways that lead them into and out of the bone marrow.
Section snippets
Bone marrow T cells: CD4 and CD8 subsets, phenotype and activation state
In both humans and mice, T-cell receptor (TCR) αβ+ cells constitute ∼3–8% of nucleated bone marrow cells 7, 8. Between 15 and 50% of the bone marrow TCR αβ+ cells belong to the natural killer T (NKT)-cell subset, the rest being canonical CD4 and CD8 mature lymphocytes 7, 8. The CD4:CD8 ratio in the bone marrow is ∼1:2, which, in comparison with the ratio found in both peripheral lymph nodes and the blood, is inverted, in that the latter ranges from 2:1 to 2.5:1 7, 8. The bone marrow also
Memory T cells migrate to the bone marrow
As early as 1974 it was documented that mouse CD4 cells migrate to the bone marrow after priming and it was proposed that bone marrow CD4 cells contributed to the development of a memory antibody response in this organ [16]. Many years later, it was shown that human bone marrow grafts from immunised donors contain anti-tetanus memory CD4 cells, which persist in the recipients for years following transplantation [17]. Subsequent studies demonstrated the presence of memory CD8 cells in the bone
Adhesion molecules and chemokines regulate T-cell migration to the bone marrow
T lymphocytes circulating in the blood can enter the bone marrow by crossing flat endothelium-lined vessels. Similarly to other leukocytes migrating from the blood stream into tissues, T cells first roll and attach to the endothelium through selectin- and integrin-mediated contacts. On the endothelium, the interaction of T cells with locally retained chemokines results in T-cell integrin activation. This leads to the firm adhesion step and subsequent T-cell migration across the vascular
T cells emigrate from the bone marrow
Although the rules governing bone marrow T-cell trafficking are not yet completely understood, it has long been known, from our studies of in situ labelling of the bone marrow by local selective perfusion in pigs [33] and sheep [34], that bone marrow T cells re-circulate from the bone marrow to other lymphoid organs. However, nothing is known about the signals regulating T-cell exit from the bone marrow. This must occur through blood vessels because no lymphatics drain this organ. It would be
The bone marrow can prime naïve T cells
Primary T-cell responses to blood-borne antigens can be initiated in the bone marrow (Figure 1b). This was shown initially in conditions of altered lymphocyte trafficking in splenectomised mice [38] and then in individuals with normal lymphoid organs, for both CD4-cell and CD8-cell responses [39]. Thus, the bone marrow resembles a secondary lymphoid organ (i.e. a site of T-cell priming), although it lacks the organised T- and B-cell areas found in the spleen and lymph nodes. Clusters of
The bone marrow recruits effector T cells
The bone marrow contains virus-specific CD8 cells during the course of infections by several viruses that localise within this organ, such as LCMV in mice, SIV in monkeys and HIV in humans 18, 41, 42 (Figure 1c).
In certain haematological malignancies, such as the monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma, CD4 and CD8 cells reactive against tumour cells have been found in the bone marrow of non-immunised patients 2, 43 (Figure 1c). Other studies reported the
T-cell migration to the bone marrow as opposed to secondary lymphoid and extra-lymphoid organs
It is not clear yet whether the memory T cells that home to the bone marrow migrate along a re-circulatory pathway including other organs, and, if so, which organs are included.
A recent report shows that, following parabiosis (i.e. a surgical technique enabling the blood circulation to be connected between two mice), blood-borne memory CD8 cells rapidly equilibrate into spleen, lymph nodes, bone marrow, lung and liver, whereas their entry is delayed into intestinal lamina propria, brain and
Concluding remarks and future directions
The studies reviewed here document that the bone marrow functions not only as a primary, B lymphocyte-producing organ but also as a secondary lymphoid organ for CD4- and CD8-cell responses, as well as a site of preferential homing and persistence for memory T cells (Box 1). We have focussed on evidence showing that memory CD8 cells preferentially migrate to the bone marrow and proliferate in this organ; however, it might be that an increased retention or a better survival contributes to the
Acknowledgements
We thank A. Santoni and I. Borrello for reading the manuscript and the Immunology group at the IGB-IBP (particularly G. Cassese and E. Parretta) for discussion. We would like to thank Sheila Fryk for polishing the English. The work in the F. D. laboratory is supported by grants from the EU (Project N°. QLK2-CT-2002-0062, EPI-PEP-VAC), Italian Government (FIRB 2001, Project N°. RBNE01RB9B) and the Italian Association for Cancer Research (AIRC). The experiments of R. P. were supported by the
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