The bone marrow: a nest for migratory memory T cells

doi:10.1016/j.it.2005.04.011

Trends in Immunology

Volume 26, Issue 7, July 2005, Pages 360-366

https://doi.org/10.1016/j.it.2005.04.011 Get rights and content

It has been known for a long time that T-cell precursors generated in the bone marrow migrate to the thymus, where T-cell development occurs. However, a fact often neglected is that, under physiological conditions, mature CD4 and CD8 lymphocytes undergo extensive migration from the blood to the bone marrow and vice versa. Here, we first review several observations showing that the bone marrow can function as a secondary lymphoid organ for both CD4 and CD8 cells, as well as a preferential homing site for memory T cells. Second, we discuss evidence that, a long time after priming, memory CD8 cells proliferate more extensively in the bone marrow than they do in either secondary lymphoid or extra-lymphoid organs. Finally, we propose that the bone marrow is a central organ in mature T-cell traffic and contributes greatly to long-term cytotoxic memory, which has implications for adoptive immunotherapy and vaccine design.

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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Trends in Immunology

The bone marrow: a nest for migratory memory T cells

Introduction

Section snippets

Bone marrow T cells: CD4 and CD8 subsets, phenotype and activation state

Memory T cells migrate to the bone marrow

Adhesion molecules and chemokines regulate T-cell migration to the bone marrow

T cells emigrate from the bone marrow

The bone marrow can prime naïve T cells

The bone marrow recruits effector T cells

T-cell migration to the bone marrow as opposed to secondary lymphoid and extra-lymphoid organs

Concluding remarks and future directions

Acknowledgements

Immunity

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Blood

Immunity

Cell. Immunol.

Blood

Blood

Blood

Blood

Blood

Immunity

Immunol. Today

Immunol. Today

Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow

Nat. Med.

Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy

J. Exp. Med.

CD4 lymphocytes in the blood of HIV+ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion

J. Leukoc. Biol.

T-cell function and migration. Two sides of the same coin

N. Engl. J. Med.

Lymphocyte trafficking across high endothelial venules: dogmas and enigmas

Nat. Rev. Immunol.

Distribution of lymphocyte subsets and natural killer cells in the human body

Clin. Investig.

Characterization of a newly discovered T-cell receptor β-chain heterodimer expressed on a CD8+ bone marrow subpopulation that promotes allogeneic stem cell engraftment

Nat. Med.

Of mice and not men: differences between mouse and human immunology

J. Immunol.

Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vβ repertoire

Eur. J. Immunol.

Bone marrow CD8 T cells are in a different activation state than those in lymphoid periphery

Eur. J. Immunol.

Phenotype analysis of lymphocyte subsets in normal human bone marrow

Am. J. Clin. Pathol.

Restricted TCR repertoire and long-term persistence of donor-derived antigen-experienced CD4+ T cells in allogeneic bone marrow transplantation recipients

J. Immunol.

Preferential localization of effector memory cells in nonlymphoid tissue

Science

CD4 lymphocytes in the blood of HIV⁺ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion

Characterization of a newly discovered T-cell receptor β-chain heterodimer expressed on a CD8⁺ bone marrow subpopulation that promotes allogeneic stem cell engraftment

Characterization of CD4⁺ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vβ repertoire

Restricted TCR repertoire and long-term persistence of donor-derived antigen-experienced CD4⁺ T cells in allogeneic bone marrow transplantation recipients