Maintenance of memory CD8 T cells: Divided over division

Abstract

Once generated during an infection, memory CD8+ T cells can provide long-lasting protection against reinfection with an intracellular pathogen, but the longevity of this defense depends on the ability of these pathogen-specific memory cells to be maintained. Figure 1. Siracusa et al. [13] show that in the spleen, CD8 memory T cells are rapidly depleted upon CyP treatment, as they undergo homeostatic proliferation. In contrast, CD8 memory T cells in the BM are mostly quiescent, and thus protected from immediate depletion by CyP. These differences could be due to the supporting cell types that are present in spleen and bone marrow (e.g, more dendritic cells in the spleen), and/or differential expression of homeostatic cytokines.which are rapidly killed by CyP treatment (Fig. 1). Importantly, by treating mice with the drug FTY720, which inhibits egress of lymphocytes from lymphoid organs, the authors demonstrate that maintenance of memory CD8 T cells in the BM upon CyP treatment is not caused by a compensatory influx of peripheral CD8 T cells. A caveat of the study is that CyP also has some non-specific side-effects: CyP can deplete proliferating Tregs that in turn affect T cell homeostasis [15], and CyP has been shown to induce type 1 interferon and thereby increase proliferation of CD8 + memory T cells [16]. Nevertheless, the findings of Siracusa et al.[13] challenge our view on how memory CD8 T cells are maintained and suggest that the underlying mechanism may differ per organ. The conclusion that CD8 memory T cells in the BM are quiescent and do not proliferate, opposes previous studies from other groups regarding the maintenance of CD8 memory T cells in the BM. The group of Francesca di Rosa has published two papers showing that BM CD8 memory T cells contain a higher percentage of proliferating cells than their counterparts in either the spleen or lymph nodes, and this group proposed that the BM acts as a niche for antigen-independent proliferation of CD8 memory T cells [17,18]. Two other studies, of which one was in non-human primates, came to the same conclusion that homeostatic proliferation of memory CD8 T cells is most profound in the BM [12,19]. The discrepancies between the results of the Radbruch group and other groups regarding the proliferation of CD8 memory T cells in the BM remain unresolved, and could be due to many different factors. One key issue is the suspected induction of proliferation by BrdU treatment [10,18]. Most studies that have claimed higher proliferation of CD8 memory T cells in the BM as compared to the spleen, have done so based on BrdU incorporation by CD8 memory T cells [12,17,18]. In their 2015 study, Radbruch and colleagues showed that a 3 day treatment of 1 mg/mL BrdU in drinking water supplemented with sugar (which increases water consumption [20]) is sufficient to induce CD8 memory T-cell proliferation, with up to 75% of all CD8 memory T cells in the BM and spleen proliferating [10]. Of note, these percentages were much higher than those reported by the aforementioned stud...

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.…”

Connecting with the immunological community

“…As a case in point, we published two papers reaching contradictory conclusions about the role of RIPK3 and MLKL signaling in NET formation along with a Commentary . We also published a paper on the role of homeostatic proliferation in CD8 + memory T lymphocyte generation knowing that a previous paper from the same group on the topic had already generated a lot of discussion ; a Commentary highlighting the pros and cons of the study was published alongside the article. We appreciate that the article was from an ExCo member, and that ExCo and Board members regularly publish in EJI, but I want to stress that all papers are externally reviewed before a decision is reached and the review process is published online for all to see .…”

Commentary: Maintenance of CD8+ T Memory Lymphocytes in the Spleen but Not in the Bone Marrow Is Dependent on Proliferation

“…Moreover, they claim that memory CD8 T cells are resident in the BM, based on the results of a combination treatment with CyP and FTY720, a S1P receptor modulator that blocks cell egress from lymphoid organs. In the same issue of Eur J Immunol , Nolte et al commented the findings by Radbruch and coworkers, highlighting their novelty and potential implications for the clinic ( 2 ). In this commentary, we would like to offer a different perspective, from a point of view that includes previous kinetics issues on CD8 T cell renewal in the BM and on the homeostatic regulation of memory T cells after an insult.…”

“…We would like to particularly highlight some possible CyP indirect effects on CD8 T cells that were not taken into consideration. CyP induces type I IFN that in turn can regulate CD8 T cell homeostatic proliferation ( 24 ) and inhibit Treg cells ( 20 , 25 ), possibly unleashing memory CD8 T cells from the Treg-mediated enforcement of their quiescent state ( 2 , 26 ).…”