Peripheral antibody concentrations are associated with highly differentiated T cells and inflammatory processes in the human bone marrow

Abstract

Background Antigen-experienced immune cells migrate back to the bone marrow (BM), where they are maintained in BM survival niches for an extended period. The composition of T cell subpopulations in the BM changes with age, leading to an accumulation of highly differentiated T cells and a loss of naïve T cells. While innate immune cells are also affected by age, little is known about interactions between different adaptive immune cell populations maintained in the BM. In this study, the phenotype and function of innate and adaptive immune cells isolated from human BM and peripheral blood (PB) was analysed in detail using flow cytometry, to determine if the accumulation of highly differentiated T and B cells, supported by the BM niches, limits the maintenance of other immune cells, or affects their functions such as providing protective antibody concentrations. Results Total T cells increase in the BM with age, as do highly differentiated CD8 + T cells which no longer express the co-stimulatory molecule CD28, while natural killer T (NKT) cells, monocytes, B cells, and naïve CD8 + T cells all decrease in the BM with age. A negative correlation of total T cells with B cells was observed in the BM. The percentage of B cells in the BM negatively correlated with highly differentiated CD8 + CD28 − T cells, replicative-senescent CD8 + CD57 + T cells, as well as the CD8 + CD28 − CD57 + population. Similar correlations were seen between B cells and the frequency of highly differentiated T cells producing pro-inflammatory molecules in the BM. Interestingly, plasma concentrations of diphtheria-specific antibodies negatively correlated with highly differentiated CD8 + CD57 + T cells as well as with exhausted central memory CD8 + and CD4 + T cells in the BM. A negative impact on diphtheria-specific antibodies was also observed for CD8 + T cells expressing senescence associated genes such as the cell cycle regulator p21 (CDKN1A), KLRG-1, and elevated levels of reactive oxygen species (ROS). Conclusion Our data suggest that the accumulation and maintenance of highly differentiated, senescent, and exhausted T cells in the BM, particularly in old age, may interfere with the survival of other cell populations resident in the BM such as monocytes and B cells, leading to reduced peripheral diphtheria antibody concentrations as a result. These findings further highlight the importance of the BM in the long-term maintenance of immunological memory. Electronic supplementary material The online version of this article (10.1186/s12979-019-0161-z) contains supplement...

CD28 and CD57 define four populations with distinct phenotypic properties within human CD8+ T cells

“…As CMV has been shown to drive T cells to terminal differentiation [32,33], the frequency of CD28 + CD57 − , DP, DN, and CD28 − CD57 + CD8 + T cells in the PB of CMV seropositive and seronegative persons of different age was compared. Similar to previous results, CD28 + CD57 − cells decreased and CD28 − CD57 + cells increased during aging in CMV − and CMV + persons [18]. We showed that the overall frequency of DP cells within CD8 + T cells did not change with age, but, when the samples were divided into CMV − and CMV + persons, DP CD8 + T cells increased significantly with age in CMV − donors (Fig.…”

“…1B). CD28 + CD57 − CD8 + T cells decrease with age whereas CD28 − CD57 + CD8 + T cells increase (data not shown), corroborating earlier reports [15][16][17] and results in our group [18]. Whether age also affects the frequencies of DP and DN CD8 + T cells is currently unknown.…”

“…While intermediate expression of effector molecules is required for CD8 + T cell functions, an overproduction may be detrimental. Indeed, a negative correlation of diphtheria‐specific antibody concentrations in the plasma with the frequency of CD28 − CD57 + CD8 + T cells and IFN‐γ + CD28 − CD57 + CD8 + T cells was recently observed by our group . In addition, a small amount of DP cells may lose CD28 from the surface and differentiate into CD28 − CD57 + cells.…”

The immune response to influenza in older humans: beyond immune senescence

“…A recent study of adults undergoing elective hip replacement has also shown the importance of the bone marrow environment in maintaining memory and effector cells and how the accumulation of both highly differentiated and terminally differentiated CD8 T cells is associated with declining serum antibody titers against diphtheria. This appears to be related to increased numbers of terminally differentiated CD8 T cells which negatively affect the maintenance of B cells and plasma cells, while increases in highly differentiated CD8 T cells lead to heightened proinflammatory cytokine levels and potentially toxic effects on B cell maintenance [36].…”

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

“…The telomere length of these cells is usually considerably shortened and oligoclonality in the T cell repertoire may ensue [44]. The inflation of the memory T cell pool may also contribute to an impaired immune response by occupying the "immunological space" (the total number of cell niches available in e.g., bone marrow) available [45]. The lifetime exposure to pathogens is driving the expansion of memory T cells.…”