Discussion
In the current study, we found that although the percentages of BM ECs
in young and old donors were comparable, BM ECs from young donors had
significantly lower ROS levels and better
migratory
and tube-forming abilities than those from old donors, which was in
accordance
with previous murine and human circulating blood studies about EC
ageing[33, 34]. Moreover, young ECs regulated T cells
differentiation into more balanced Th1, Th2, Tc1 and Tc2 cells than old
ECs. Reduced levels of T cell activation molecules and inflammatory
cytokines in young BM ECs may be the possible mechanism
underlying
of the balanced immunomodulatory effects of young ECs (Fig. 6). Studies
have shown that ECs can stimulate purified T cell proliferation without
the involvement of other antigen-presenting cells, as ECs express major
histocompatibility complex class I and II molecules and innate immune
receptors and
secrete
inflammatory mediators[18, 35, 36]. Human ECs were found to induce
programmed death ligand-1 expression on Tregs and thus enhance the
suppressive ability of Tregs[15]. One murine study demonstrated
pretreatment of EC with palmitoyl-3-cysteine-serine-lysine-4 (TLR1/2
ligand) reverted the suppressive properties of T cells and triggered
virus-specific CD8+ T cell immunity[17]. Notably,
destruction
of the EC barrier triggered T cell
costimulation
and led to the activation of immune effectors such as Th1 and Tc1 cells
and the release of inflammatory mediators to destroy infected
cells[14]. In the present study, young BM ECs exhibited lower
expression of T cell activation receptors such as TLRs, fewer
costimulatory molecules such as CD80, fewer chemokine receptors and
ligands such as CCR5 and CXCL10, and fewer inflammatory cytokines such
as PRF1 and NLRP3 than old BM ECs. Therefore, combining previous
reports[14-18, 35, 36] and the current study, we hypothesize that
the different immunomodulatory effects of ECs from young and old
individuals may lead to T cell subset alterations with ageing.
Furthermore, the increased TLR
signalling
pathways and costimulatory molecules and chemokines in ECs from older
individuals might be one of the underlying reasons for the imbalance in
effector T cell subsets.
T cell subset disparities have been found to affect the incidence of
acute graft-versus-host disease (aGVHD), a common and
life-threatening complication after
allogeneic haematopoietic stem cell transplantation[37-41]. Numerous
studies have shown that the occurrence of aGVHD was related to increased
frequencies of donor Th1 and Tc1 cells and reduced frequencies of Th2
and Tc2 cells[37, 38, 41]. Furthermore, we recently reported that
young donors had lower percentages of Th1 and Tc1 cells than old
donors[5], which could partly explain why patients receiving
transplants from young donors showed less aGVHD than those who received
transplants from old donors[42, 43]. However, the in-depth reason
why the aGVHD incidence was affected by donor age remains to be
explored. It is worth noting that our study and other previous studies
indicated that the number and function of ECs were damaged, EC ROS
levels were increased in aGVHD patients, and EC destruction could
predict the severity of aGVHD[23, 44]. Moreover, our current data
demonstrated that ECs from younger donors could instruct T cells to
generate more balanced Th1/Th2 and Tc1/Tc2 cell ratios. Thus, we
hypothesize that the different effects on T cells by ECs from donors of
different ages might affect the occurrence of aGVHD in patients after
allo-HSCT.
We are aware, however, that the mechanism by which T cell subsets change
with ageing is heterogeneous. It would be more rigorous and
informative
to further explore whether T cell activation molecules in BM ECs in
donors of different ages directly impact effector T cell subset
differentiation.
In summary, the current study indicated lower EC ROS levels, better BM
EC functions, and more balanced T cell modulating effects of BM ECs from
young donors than from old donors. Our preliminary data showed that
lower TLR signalling and costimulatory molecules as well as chemokine
and receptor expression, and less inflammatory cytokine secretion in the
ECs of young individuals might cause young ECs to induce more balanced T
cell subset differentiation than old ECs. Although further validation is
required, our results may provide a new prospective to better understand
the mechanism of effector T cell subset alterations with ageing.