Introduction
The
immune system undergoes
a
series of physiological functional declines with ageing, which are
termed
immunosenescence
and
partly
result in poor responses to vaccines and increased incidence of severe
infectious diseases and cancer in the elderly population[1, 2]. Some
studies have shown that
the
adaptive immune system, especially T cells, is more susceptible to
ageing than the innate immune system[3, 4]. Our and other previous
studies showed decreased frequencies of bone marrow (BM) lymphoid
progenitor cells and naïve T cells but increased frequencies of memory T
cells, as well as unbalanced effector T cell subset differentiation,
such as increased T helper (Th)-1 and T cytotoxic (Tc)-1 cells, in
elderly individuals[1, 2, 5]. Emerging evidence has indicated that
decreased BM lymphoid progenitor cells and
involution
of the thymus may be responsible for the alterations in T cell subsets
with ageing[6-8]. However, the underlying mechanism of the more
balanced differentiation of effector T cell subsets in young individuals
than in elderly individuals remains to be clarified.
The BM, as both a primary and secondary lymphoid organ, plays an
essential role in regulating the development and differentiation of T
cells[9]. Endothelial cells (ECs), which line the interior of blood
and lymphatic vessels, are
instructive
components of the BM microenvironment[10].
In
addition to supporting self-renewal and lineage-specific differentiation
of haematopoietic stem cells through the release of specific angiocrine
factors[11-13], ECs also play crucial immunological roles,
particularly in T cell recruitment and activation[14, 15]. Emerging
evidence has suggested that ECs exhibit a semi-professional
antigen-presenting cell phenotype by expressing classic innate immune
receptors such as Toll-like receptors (TLRs), NOD-like receptors, and
inducible costimulatory ligands[16-18]. Although controversial, some
studies have suggested that ECs express costimulatory molecules such as
CD80 and CD86[19, 20]. Activation of EC TLRs by lipopolysaccharide
(LPS) or lipopeptide upregulated the secretion of specific cytokines,
chemokines and adhesion molecules and increased the recruitment and
activation of T cells[14, 15]. In addition, recent studies
demonstrated that ECs were able to suppress T cell proliferation and
modulate T cells to produce fewer proinflammatory cytokines through
tumour
necrosis factor and its receptor 2 signalling pathway[10]. Moreover,
liver sinusoidal ECs have been shown to modulate naïve
CD8+ T cells to secrete less interferon-γ (IFN-γ) and
interleukin (IL)-2 by cross-presentation to CD8+ T
cells, which then induces immune tolerance[21, 22]. However, whether
the frequency and functions of BM ECs, especially
their
capacity to regulate effector T cell subsets, differ between young and
old individuals remains to be clarified.
Therefore, the current study was performed to evaluate the frequency and
reactive oxygen species (ROS) levels of BM ECs among
young,
middle-aged, and old healthy individuals. Moreover, we investigated
whether the function of BM ECs, especially their capacity to modulate
the differentiation of effector T cell subsets, differs between young
and old individuals and the underlying mechanism of this
immunomodulatory discrepancy. Our study may contribute to improving the
understanding of T cell subset alterations with ageing.