Memory CD8⁺ T cells colocalize with IL‐7⁺ stromal cells in bone marrow and rest in terms of proliferation and transcription

Abstract

It is believed that memory CD8+ T cells are maintained in secondary lymphoid tissues, peripheral tissues, and BM by homeostatic proliferation. Their survival has been shown to be dependent on IL-7, but it is unclear where they acquire it. Here we show that in murine BM, memory CD8+ T cells individually colocalize with IL-7+ reticular stromal cells. The T cells are resting in terms of global transcription and do not express markers of activation, for example, 4-1BB (CD137), IL-2, or IFN-γ, despite the expression of CD69 on about 30% of the cells. Ninety-five percent of the memory CD8+ T cells in BM are in G0 phase of cell cycle and do not express Ki-67. Less than 1% is in S/M/G2 of cell cycle, according to propidium iodide staining. While previous publications have estimated the extent of proliferation of CD8+ memory T cells on the basis of BrdU incorporation, we show here that BrdU itself induces proliferation of CD8+ memory T cells. Taken together, the present results suggest that CD8+ memory T cells are maintained as resting cells in the BM in dedicated niches with their survival conditional on IL-7 receptor signaling.

Immunological memories of the bone marrow

“…However, these results should be interpreted cautiously. We could show that BrdU induces at least some of the proliferation it measures in antigen‐experienced CD8 + memory T cells 117. 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.…”

“…According to staining of Ki‐67, more than 90% of murine bone marrow memory CD8 + T cells are in G0 of the cell cycle, more than 180 days after the onset of an intentional immune response, and less than 0.5% are in the S/G2/M phases of cell cycle 117. The same is true for human memory CD8 + and CD4 + T cells of bone marrow 33.…”

“…Their transcriptomes are those of resting cells 33, 59, 81, 117. CD8 + memory T cells of the bone marrow express only about 0.6 pg of RNA per cell, as compared to activated CD8 + T cells, which express more than 10 pg of RNA per cell 117.…”

“…This observation also suggests that the lifestyle of resident memory T cells of the bone marrow might be not so different from the lifestyle of memory plasma cells. In murine bone marrow, memory CD4 + and CD8 + T lymphocytes are found in close association if not direct contact with stromal cells 59, 117, 137, 145. They are individually dispersed throughout the parenchyme 117.…”

“…Average distances between any 2 CD4 + or 2 CD8 + memory T cells are the same as those between any 2 CD4 + and CD8 + memory T cells, suggesting that they compete for the same niches. And both, CD4 + and CD8 + memory T cells of the bone marrow are docking onto stromal cells expressing the adhesion molecule VCAM‐1 and the cytokine IL‐7 59, 117. Both, CD4 + and CD8 + memory T cells of bone marrow express VLA‐4, a receptor for VCAM‐1 and fibronectin.…”