Bone marrow CD8 cells down-modulate membrane IL-7Rα expression and exhibit increased STAT-5 and p38 MAPK phosphorylation in the organ environment.

Abstract

By comparing mature CD8-cell turnover in different organs, we previously demonstrated that CD8 cells proliferate predominantly in the bone marrow (BM). To investigate the mechanisms underlying such increased turnover, we compared BM, lymph nodes, and spleen CD8 cells from untreated C57BL/6 mice regarding in vivo proliferation within the organ; in vitro response to interleukin-7 (IL-7), IL-15, IL-21; ex vivo expression of membrane CD127 (IL-7Ralpha), intracellular Bcl-2, phospho-STAT-5 (signal transducer and activator of transcription 5), phospho-p38 mitogen activated protein kinase (MAPK); and in vivo proliferation on adoptive transfer. In the BM, the proliferation rate was increased for either total CD8 cells or individual CD44 and CD122 subsets. In contrast, purified CD8(+) cells from the BM did not show an enhanced in vitro proliferative response to IL-7, IL-15, and IL-21 compared with corresponding spleen cells. After transfer and polyinosinic-polycytidylic acid (polyI:C) treatment, both spleen-derived and BM-derived CD8 cells from congenic donors proliferated approximately twice more in the recipient BM than in spleen and lymph nodes. Our results suggest that BM CD8 cells are not committed to self-renewal, but rather are stimulated in the organ. Molecular events constantly induced in the CD8 cells within the BM of untreated mice include increase of both phosphorylated STAT-5 and phosphorylated p38 intracellular levels, and the reduction of CD127 membrane expression.

IL-15–Dependent Upregulation of GITR on CD8 Memory Phenotype T Cells in the Bone Marrow Relative to Spleen and Lymph Node Suggests the Bone Marrow as a Site of Superior Bioavailability of IL-15

“…This finding not only argues against the possibility that GITR hi and GITR lo cells are different subsets of T cells within the spleen versus bone marrow, or that IL-15 is required to maintain a unique subset of memory T cells that is resident in the bone marrow, but rather it suggests that GITR upregulation in the bone marrow reflects the local microenvironment. Our data concur with studies from Di Rosa and colleagues (21,22), which indicate that despite the lack of recent Ag exposure, bone marrow CD8 memory T cells have a more activated phenotype than do their counterparts in other organs. They also demonstrated that although homeostatic proliferation is augmented in the bone marrow, CD8 memory T cells in this organ do not have an intrinsic ability for enhanced cytokine-mediated proliferation, suggesting that they are stimulated to proliferate locally in the bone marrow (21).…”

“…Our data concur with studies from Di Rosa and colleagues (21,22), which indicate that despite the lack of recent Ag exposure, bone marrow CD8 memory T cells have a more activated phenotype than do their counterparts in other organs. They also demonstrated that although homeostatic proliferation is augmented in the bone marrow, CD8 memory T cells in this organ do not have an intrinsic ability for enhanced cytokine-mediated proliferation, suggesting that they are stimulated to proliferate locally in the bone marrow (21). This is con- hi T cells recovered from each organ was determined.…”

“…It has been previously demonstrated that T cells in the bone marrow can have a more activated phenotype than do splenic T cells (21,22). We sought to confirm this by comparing the expression of various activation markers and cytokine receptors in both organs of unimmunized mice.…”

Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 T Cells: Parameter Estimation Based on 5-Bromo-2′-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow

“…We characterized some of the molecular events occurring in CD8 T cells within the BM, such as increased phosphorylation of the signal-transducing molecules STAT-5 and p38 MAPK and reduced membrane expression of CD127, the IL-7R ␣-chain (5). Both naive-phenotype CD44 int/low and memory-phenotype CD44 high CD8 T cells contain a higher percentage of proliferating cells in the BM than in spleen and LN (5). The important role played by the BM in mature CD8 T cell turnover becomes even more evident when the total numbers of proliferating CD8 T cells contained in the sum of spleen, LN, and BM are taken into account.…”

CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

“…Of particular interest is the BM, in which a significantly increased number of these cells was found compared with WT memory T cells. It has been shown that the survival factors IL-7 and IL-15 are expressed in the BM (23,34,35). In addition, memory CD8 T cells are reported to use IL-15 in the BM to turn over (23).…”