Plasma cell numbers decrease in bone marrow of old patients.

The BM is well understood to play a key role in plasma cell homing and survival in mice. In humans, BM plasma cells and their functions are less well characterized. In this study, we used paired bone biopsies from the femur shaft and blood samples from persons of different ages to analyze age-related changes of plasma and memory B cells. Our results demonstrated that plasma cells were mainly located in the BM, while a higher percentage of memory B cells was in the peripheral blood than in the BM. The frequency of plasma and memory B cells from both sources decreased with age, while immature and naïve B cells were unaffected. An age-related decline of tetanus- and diphtheria-specific BM plasma cells was observed, whereas influenza A- and cytomegalovirus-specific BM plasma cells were not affected. With the exception of cytomegalovirus, peripheral antibody concentrations correlated with BM plasma cells of the same specificity, but were independent of antigen-specific peripheral blood memory B cells. Our results demonstrate that the BM houses decreased numbers of plasma cells in old age. The number of cells of certain specificity may reflect the number and time point of previous antigen encounters and intrinsic age-related changes in the BM.

The aging bone marrow and its impact on immune responses in old age.

With aging the immune system undergoes significant age-related changes. These age-dependent changes are referred to as immunosenescence and are partially responsible for the poor immune response to infections and the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in innate and adaptive cell-mediated immune function in the peripheral blood and the bone marrow. The aging of bone marrow cells and in particular, of adaptive immune cells in the bone marrow has been addressed relatively rarely. It is therefore the goal of this review to summarize what is known about the effect of age on bone marrow immune cells and their precursors in mice and humans.

T cell receptor-mediated activation is a potent inducer of macroautophagy in human CD8(+)CD28(+) T cells but not in CD8(+)CD28(-) T cells.

A key feature of the aged human immune system is the accumulation of highly differentiated CD8(+)CD28(-) T cells, a phenomenon that negatively influences immune function in the elderly. However, the mechanisms that regulate survival or death of CD8(+)CD28(-) T cells remain incompletely understood. Macroautophagy has been shown to protect cells from unfavorable environmental conditions and extend lifespan of various cells and organisms. In this study, we investigated autophagy in CD8(+)CD28(+) and CD8(+)CD28(-) T cells following T cell receptor (TCR) engagement. We demonstrate that TCR-mediated activation led to a potent induction of autophagy in CD8(+)CD28(+) T cells which was accompanied by an increased activity of the mammalian target of rapamycin complex 1 (mTORC1). This was surprising, as mTORC1 is generally perceived as an inhibitor of autophagy. Inhibition of mTORC1 by rapamycin could still enhance activation-induced autophagy. In contrast, CD8(+)CD28(-) T cells induced autophagy to a significantly lower extent in response to TCR engagement compared to CD8(+)CD28(+) T cells and failed to increase autophagy upon mTORC1 inhibition. In conclusion, we describe for the first time the induction of autophagy in human CD8(+) T cells following TCR engagement and the decreased ability of CD8(+)CD28(-) T cells to induce autophagy, suggesting that they cannot meet the metabolic needs of antigen receptor-mediated activation and are therefore unlikely to survive when confronted by their specific antigens.

Bone marrow T cells from the femur are similar to iliac crest derived cells in old age and represent a useful tool for studying the aged immune system.

BACKGROUND: CD4+ and CD8+ T cells reside in the human bone marrow (BM) and show a heightened activation state. However, only small sample sizes are available from sources such as the iliac crest. Larger samples can be obtained from the femur in the course of hip replacement surgery. It was therefore the goal of the present study to compare the phenotype and function of BM T cells from different sources from elderly persons and to investigate how femur derived bone marrow T cells can serve as a tool to gain a better understanding of the role of adaptive immune cells in the BM in old age. RESULTS: Bone marrow mononuclear cells (BMMC) were isolated from either the iliac crest or the femur shaft. As expected the yield of mononuclear cells was higher from femur than from iliac crest samples. There were no phenotypic differences between BMMC from the two sources. Compared to PBMC, both BM sample types contained fewer naïve and more antigen experienced CD4+ as well as CD8+ T cells, which, in contrast to peripheral cells, expressed CD69. Cytokine production was also similar in T cells from both BM types. Larger sample sizes allowed the generation of T cell lines from femur derived bone marrow using non-specific as well as specific stimulation. The phenotype of T cell lines generated by stimulation with OKT-3 and IL-2 for two weeks was very similar to the one of ex vivo BM derived T cells. Such lines can be used for studies on the interaction of different types of BM cells as shown by co-culture experiments with BM derived stromal cells. Using CMVNLV specific T cell lines we additionally demonstrated that BM samples from the femur are suitable for the generation of antigen specific T cell lines, which can be used in studies on the clonal composition of antigen specific BM T cells. CONCLUSION: In conclusion, our results demonstrate that BMMC from the femur shaft are a useful tool for studies on the role of T cells in the BM in old age.