Bone Marrow T Cells and the Integrated Functions of Recirculating and Tissue-Resident Memory T Cells

Abstract

Changes in T cell trafficking accompany the naive to memory T cell antigen-driven differentiation, which remains an incompletely defined developmental step. Upon priming, each naive T cell encounters essential signals – i.e., antigen, co-stimuli and cytokines – in a secondary lymphoid organ; nevertheless, its daughter effector and memory T cells recirculate and receive further signals during their migration through various lymphoid and non-lymphoid organs. These additional signals from tissue microenvironments have an impact on immune response features, including T cell effector function, expansion and contraction, memory differentiation, long-term maintenance, and recruitment upon antigenic rechallenge into local and/or systemic responses. The critical role of T cell trafficking in providing efficient T cell memory has long been a focus of interest. It is now well recognized that naive and memory T cells have different migratory pathways, and that memory T cells are heterogeneous with respect to their trafficking. We and others have observed that, long time after priming, memory T cells are preferentially found in certain niches such as the bone marrow (BM) or at the skin/mucosal site of pathogen entry, even in the absence of residual antigen. The different underlying mechanisms and peculiarities of resulting immunity are currently under study. In this review, we summarize key findings on BM and tissue-resident memory (TRM) T cells and revisit some issues in memory T cell maintenance within such niches. Moreover, we discuss BM seeding by memory T cells in the context of migration patterns and protective functions of either recirculating or TRM T cells.

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

“…In fact, there is ample evidence for continuous migration of CD8 + T cells to and from the BM over longer periods of time [28,38]. This rather suggests that CD8 + T cells use perivascular niches in the BM as a temporary stopping point before they migrate elsewhere [38]. In conjunction with the findings by Chaix et al [20], we postulate that CXCR4 may be essential for homeostatic proliferation and/or maintenance of CD8 + T cells, as it guides these cells toward specialized CXCL12 high stromal niches, which we found to be rich in the supporting cytokines IL-7 and IL-15.…”

Immunological memories of the bone marrow

“…Where the antigen‐experienced T cells of the circulating memory obtain the signals to proliferate, die, or exit a particular tissue is unclear. It has been discussed that the bone marrow may provide a hub for circulating memory T lymphocytes 103. IL‐7‐expressing cells are abundant also in the gut and in the lymphoid organs104 as are professional antigen‐presenting cells 105, 106…”

“…Feeding mice with BrdU resulted in a marked increase in Ki‐67 + CD8 + memory T cells, and cells in S/G2/M phases of cell cycle, according to staining of their DNA with propidium iodide. This was even more prominent for memory CD8 + T cells of bone marrow, a finding which led to an ongoing debate on the nature and lifestyle of memory T cells in the bone marrow 103, 118, 119, 120, 121, 122, 123, 124…”

Crucial role for CD69 in allergic inflammatory responses: CD69‐Myl9 system in the pathogenesis of airway inflammation

“…In addition to CD8 + T RM cells, resting memory CD4 + T cells in the BM require CD69 expression for their recruitment and maintenance in BM (Table ). It has been reported that, in an immune response, memory T cells preferentially reside and rest on stromal niches of the BM, suggesting that the BM works as a “reservoir” for long‐lived memory T cells .…”

“…In addition to CD8 + T RM cells, resting memory CD4 + T cells in the BM require CD69 expression for their recruitment and maintenance in BM (Table ). It has been reported that, in an immune response, memory T cells preferentially reside and rest on stromal niches of the BM, suggesting that the BM works as a “reservoir” for long‐lived memory T cells . Because we identified Myl9 in BM lysates as a CD69 ligand by pull‐down assay using the murine CD69 extracellular domain, it is likely that the CD69‐Myl9 system may also work in the recruitment and maintenance of memory CD4 T cells in the BM, although Myl9‐expressing cells to recruit CD69 + cells into the BM should be identified.…”