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.