Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Abstract

Six years ago, Radbruch and colleagues discussed in Nature Reviews Immunology (Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10, 193-200 (2010)) 1 how distinct stromal cell subsets in the bone marrow can support the lifelong persistence of plasma cells and memory T cells. These authors proposed that the bone marrow might serve as a depot for resting noncirculating memory T cells. Furthermore, they discussed how memory T cells might be maintained in the bone marrow by survival factors, such as interleukin-7 (IL-7), as opposed to by proliferative factors, such as IL-15. This view was in contrast with the largely accepted notion at the time that recirculating memory T cells are maintained by a homeostatic equilibrium between proliferation and death long after antigen clearance 2 . Furthermore, it did not accommodate previous data concerning the proliferation 3,4 and recirculation 5,6 of memory CD8 + T cells in the bone marrow.Recently, the idea that was originally proposed in Nature Reviews Immunology 1 was revived by the identification of quiescent, non-migratory tissue-resident memory T (T RM ) cells in the skin, gut and other organs 7 . Indeed, Radbruch et al. hypothesized that bone marrow memory T cells might share several features with T RM cells, and they suggested that their previous and newly generated findings supported this concept 8,9 . However, it might be misleading to chiefly consider bone marrow memory T cells as non-circulating, non-dividing cells.Experiments using Ki67 staining in mice and humans have shown that, at any given time-point, 95-98% of memory CD8 + T cells in the bone marrow are in the G0 phase of the cell cycle 8,9 . Of the remaining cells, some are in the G1 interval, and a few (that is, 0.2-1.7%) are actively proliferating in S/G2/M 3,8,9 . However, this still means that the proportion of memory CD8 + T cells proliferating in the bone marrow is reproducibly two-to fourfold higher than the proportions (that is, 0.05-0.80%) proliferating in the spleen, lymph nodes or blood 3,8,9 . This is true also when cell division is measured for one or more days. For example, in a 3 day-bromodeoxyuridine (BrdU)-labelling analysis, the average frequency of dividing antigen-specific memory CD8 + T cells was 4% in the bone marrow and 2% in the spleen 4 . Moreover, when carboxyfluorescein succinimidyl ester (CFSE)-labelled antigen-specific memory CD8 + T cells were transferred into non-immunized animals, they showed higher rates of proliferation in the bone marrow than in the spleen and lymph nodes 3,10 . In general, the data concerning memory CD8 + T cell cycling in the bone marrow are all in agreement. However, memory CD4 + T cell proliferation requires further investigation, as antigen-specific cells have not been examined in the bone marrow 11 .Despite the apparent consistency of the data concerning memory CD8 + T cells, their interpretations differ. Radbruch's group proposes that these data suggest similarity between bone marrow memory CD8 + T cells and peripheral...

Antigen‐specific CD8 T cells in cell cycle circulate in the blood after vaccination

“…A single study in humans did use DNA staining and found that an average of <0.1% of memory‐phenotype CD8 T cells were in S‐G 2 /M in the blood of donors with no systemic diseases . The interpretation at that time was that blood‐derived memory CD8 T cells are resting . Our interpretation is instead that the cells in S‐G 2 /M could have been newly activated cells responding to an environmental antigen.…”

“…36 The interpretation at that time was that blood-derived memory CD8 T cells are resting. 36,38,39 Our interpretation is instead that the cells in S-G 2 /M could have been newly activated cells responding to an environmental antigen. We suggest that the widespread use of our technical approach might prevent incomplete data analysis and/or biased interpretations.…”

CXCR4, but not CXCR3, drives CD8+ T‐cell entry into and migration through the murine bone marrow

“…Both cytokines are both important for CD8 + T-cell maintenance, but with a different underlying mechanism: IL-15 is a potent proliferative agent for CD8 + memory T cells [39,40], whereas IL-7 rather induces their survival [41,42]. Whether CD8 + memory T-cell maintenance in the BM depends on proliferation or survival is a matter that is currently heavily debated [3,4,6,[43][44][45][46][47]. This discussion will greatly benefit from conclusive evidence that IL-7 and/or IL-15 produced by CXCL12 high stromal cells support CD8 + T-cell maintenance in the BM, which requires conditional deletion of these cytokines from BM stromal cells.…”

Human T Cell Memory: A Dynamic View

“…In contrast to the anticipated role of T RM in other tissues—to provide local protection at sites of pathogen entry—such bone-marrow memory T cells (T BM ) are thought to contribute to systemic memory [24]. Interestingly, in many respects the phenotype of T BM resembles that of T RM cells, with relatively high expression of CD69, and low expression of S1P 1 and Klf2 [25,26].…”