A new paper in the journal Immunity reports that a substantial proportion of antigen-specific memory CD4 T cells take up residence in the bone marrow after an immune response, at least in mice. The paper adds to a growing body of evidence that the bone marrow represents a key – perhaps the key – site for the maintenance of immunological memory. It was established by Mark Slifka in 1995 that after both a primary and secondary infection with LCMV, plasma B cells preferentially migrate to the bone marrow and sustain antiviral antibody production there. More recently, it has been shown that the bone marrow also contains a major reservoir of central memory CD8 T cells and is the main site of their homeostatic proliferation.
But the picture for memory CD4 T cells has been less clear. As far back as 1974 it was reported that mouse CD4 T cells migrate to the bone marrow after priming but it wasn’t until over twenty years later that a study formally demonstrated that tetanus-specific memory CD4 T cells can be transferred from donor to recipient during bone marrow transplantation (with the number of cells increasing if the donor was immunized prior to donation). Very recently, Mirko Paiardini and colleagues from Guido Silvestri’s laboratory published a paper in Blood showing that the bone marrow supports extensive homeostatic proliferation of both memory CD4 and CD8 T cells in non-human primates.
In HIV-infected humans, there is an interesting radiolabeling study from 2002, which reported that a majority of CD4 T cells labeled ex vivo and reinfused trafficked to the bone marrow. The rate of migration was greater in HIV-infected participants compared to uninfected controls: “Another obvious finding is the increased intensity of labeled CD4 T cells in the vertebral and iliac bone marrow… The two other HIV+ subjects tested displayed similar enhanced accumulation of CD4 T cells in the bone, compared with the two other control subjects. It was also obvious that most of the labeled CD4 T cells in normal subjects migrated to bone marrow, and this was almost exclusively to vertebral and iliac marrow and not marrow in the long bones in both types of subjects.” However, literature addressing whether HIV-infected memory CD4 T cells can be found in the bone marrow appears sparse to non-existent – I tried searching PubMed without success. It is tempting to wonder if there may be some connection with the isolated reports that have occurred regarding bone marrow transplantation and putative eradication of HIV.
But to get back to the details of the new Immunity paper, a group of scientists led by Koji Tokoyoda studied CD4 responses to a variety of antigens (LCMV, ovalbumin & KLH) and report that as memory develops, the number of antigen-specific CD4 T cells in the spleen and lymph nodes declines, while numbers in the bone marrow increase (a finding that very much echoes Mark Slifka's seminal data on plasma B cells). From day 60 after antigen challenge, the majority of antigen-specific memory CD4 T cells (~80%) were found in the bone marrow and numbers remained relatively stable out to more than 134 days. Additional analyses showed that almost all of these cells were resting based on DNA content and gene expression, and they appeared to be in contact with IL-7-expressing stromal cells. The researchers also show that memory CD4 T cells from the bone marrow can support the generation of antibodies by B cells, although they state that their data suggests that this involves the migration of the cells out of the bone marrow to secondary lymphoid tissues.
The study authors argue that their data will require the revision of prior models of how memory CD4 T cells are maintained (the generally accepted model is that most memory CD4 T cells constantly recirculate while surveilling for antigens); they propose a new division of “resting versus mobilized memory.” However, there are some confusing aspects of the study (although they may only be confusing to people not steeped in murine immunology). In the discussion section at the end, it’s stated that: “central memory T cells expressing CCR7 and CD62L were not found in the bone marrow,” but no data is presented in support of the statement. Yet central memory CD4 T cells are considered to be a very important pool of memory CD4 T cells as they generate effector cells upon re-exposure to antigen (the pool of central memory CD4 T cells is also proportionally larger in humans than it is in mice). Also, in the case of CD8 T cells, it is the central memory subset that preferentially traffics through, and proliferates in, the bone marrow. Prior studies have also universally characterized bone marrow CD4 T cells as being “activated” based on phenotypic criteria, and it would have been perhaps useful for Tokoyoda and colleagues to offer more discussion of how their study may be reconciled with the existing literature.
While there are clearly many questions yet to be addressed, the emergence of the bone marrow’s role in immunological memory represents an important new front in immunology research. For additional information, there is an excellent and extensive review of the subject by Francesca Di Rosa available online in Immunology and Cell Biology (access is free of charge).
Immunity, 07 May 2009
doi:10.1016/j.immuni.2009.03.015
Professional Memory CD4+ T Lymphocytes Preferentially Reside and Rest in the Bone Marrow
Koji Tokoyoda1, Sandra Zehentmeier1, Ahmed N. Hegazy1,2, Inka Albrecht1, Joachim R. Grün1, Max Löhning1,2 and Andreas Radbruch1
1 Deutsches Rheuma-Forschungszentrum (DRFZ), Charitéplatz 1, Berlin 10117, Germany
2 Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany
Summary
CD4+ T lymphocytes are key to immunological memory. Here we show that in the memory phase of specific immune responses, most of the memory CD4+ T lymphocytes had relocated into the bone marrow (BM) within 3-8 weeks after their generation--a process involving integrin 2. Antigen-specific memory CD4+ T lymphocytes highly expressed Ly-6C, unlike most splenic CD44hiCD62L- CD4+ T lymphocytes. In adult mice, more than 80% of Ly-6ChiCD44hiCD62L memory CD4+ T lymphocytes were in the BM. In the BM, they associated to IL-7-expressing VCAM-1+ stroma cells. Gene expression and proliferation were downregulated, indicating a resting state. Upon challenge with antigen, they rapidly expressed cytokines and CD154 and efficiently induced the production of high-affinity antibodies by B lymphocytes. Thus, in the memory phase of immunity, memory helper Tcells are maintained in BM as resting but highly reactive cells in survival niches defined by IL-7-expressing stroma cells.
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