Biomedical Engineering Reference
In-Depth Information
naïve T lymphocytes. This process provides the initial stimulus for
adaptive immunity and tunes the immune response to the type of
encountered pathogen [
7
,
8
].
cDCs internalize pathogens and other extracellular material
by different mechanisms. Soluble materials, including viruses and
contents released from bacteria or parasites, are internalized by
either receptor-mediated endocytosis or micro- or macropinocy-
tosis, with the latter being highly upregulated in immature cDCs
[
9
,
10
]. cDCs are also among a number of professional phago-
cytic cell-types that are specialized to capture large particles such
as bacteria by an actin-dependent mechanism known as phagocy-
tosis [
11
]. Upon completion of phagocytosis, the internalized
particle is enclosed within a phagosome, an organelle that under-
goes progressive remodeling through a series of interactions with
the endosomal system [
12
]. This remodeling process, referred to
as phagosome maturation, provides a mechanism to kill invading
particulate organisms and to break them down through hydrolysis.
It also provides a means to allow signaling via phagosome-associated
PRRs, including Toll-like receptors (TLRs), following recruitment
of PRRs and their signaling platforms [
8
].
Phagosome maturation manifests distinct features in different
phagocytic cell types. In cDCs, the maturation of both phago-
somes and classical endosomes is skewed toward preservation of
antigenic peptides for assembly with major histocompatibility
complex (MHC) class I (MHC-I) and class II (MHC-II) mole-
cules for presentation to T cells. For example, maturing phago-
somes and endolysosomes in cDCs are less acidic than in other cell
types, at least in part due to impaired assembly of the vacuolar
ATPase and to the consumption of protons by superoxide gener-
ated by a highly active NADPH oxidase [
13
,
14
]. This restrains
proteolysis by lysosomal hydrolases and thus prolongs survival of
antigenic peptides. In addition, cDCs are specialized to form
tubules from both endolysosomes and phagosomes following TLR
stimulation. Long tubules that emerge from endolysosomes fol-
lowing stimulation with soluble TLR ligands favor the delivery of
newly assembled MHC-II-peptide complexes to the DC plasma
membrane and towards the immunological synapse with T cells
[
15
,
16
]. Similarly, we have shown that tubules form from matur-
ing phagosomes in cDCs several hours after uptake of bacteria or
TLR ligand-coated latex beads [
17
]. In contrast to the endolyso-
somal tubules, these “phagotubules” are not essential for the trans-
port of MHC-II-peptide complexes to the cell surface and do not
appear to fuse with the plasma membrane. Rather, they favor con-
tent exchange among distinct TLR signaling phagosomes within
the same DC. Content exchange favors optimal antigen presenta-
tion, likely by exposing MHC-II molecules on multiple phago-
somes to more antigen sources [
17
].
