Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

9.2 DC Properties
MHC class II compartment [30]. DCs also use alternative pathways of antigen processing
and can route exogenous antigen into the MHC class Ipathway, through a
mechanism known as cross-priming [31]. They may utilize molecules such as heat
shock proteins (e.g. hsp96) to deliver antigenic chaperoned peptides through CD91
into MHC class Icompartments [32, 33]. An alternative use of the term cross-priming
refers to the possibility that other cells, e.g. macrophages or DCs themselves,
may transfer antigen, perhaps in a modified form, to DCs.
In addition to encountering antigen, DCs are thought to require an antigen-independent
ªdangerº signal to induce a characteristic process of terminal differentiation often
referred to as ªmaturationº. These include signals from cytokines, bacteria [34,
35]s viruses [36], apoptotic or necrotic cells [28, 37, 38]. Depending on the differentiation/activating
stimulus, DCs may respond with a variety of important changes. Examples
include increased expression of MHC class II molecules and the co-stimulatory
CD80 and CD86 molecules [11]; generation of a new chemokine receptor repertoire,
especially CCR7 [39, 40]; and the induction of molecules like CD40 and the tumor
necrosis factor (TNF)-related activation-induced cytokine receptor (TRANCE-R)
essential for DC survival and stimulation [41, 42]. The down-regulation of E-cadherin
on LCs may reduce their adhesion to other epithelial cells [43]. DC migration requires
key intracellular signaling events (e.g. relB expression) and these processes
are initiated at the site of antigen exposure [44]. Functional differentiation/maturation
coincidences with the down-regulation of antigen-uptake and -processing capabilities,
and up-regulation of antigen-presenting function [45].
Upon receiving appropriate signals, the surveillance, DCs migrate from the tissues
into the afferent lymphatics. Key mediators, i. e. the so-called ªdangerº signals mentioned
above, initiate these events, but there also appears to be a substantial basal
rate of DC trafficking. The differentiating/activated DCs migrate into the T cell-rich
paracortex of the draining lymph nodes, guided by chemokines MIP-3P and SLC
[46, 47]. Again, recent data suggests that a complex set of DC subpopulations is present
in lymph node/tonsil, including a population of less-activated DCs, which
might play a role in peripheral tolerance [48].
Within the secondary lymphoid tissues, two key events occur with regard to an exogenous
antigen-driven immune response. Firstly, activated CD4 + T lymphocytes can
further mature DC through CD40±CD40 ligand (CD40L) interactions and this provides
a survival signal to the DCs [41]. Secondly, mature DCs secrete chemokines
such as DC-CKI, MDC, IL-8 and RANTES that attract naive and memory T and B
lymphocytes, respectively [49±51]. Mature DCs also secret cytokines including IL-7
[52] and IL-12 [53], which contribute to their antigen-presenting function. IL-7 can
induce CD4 and CD8 T and B lymphocyte proliferation and B lymphocyte differentiation
[54]. IL-12 biases T helper responses toward a Th1 effector immune response
[55]. In secondary lymphoid tissues, a stimulatory cytokine/chemokine milieu produced
by mature DCs, combined with the presentation of peptide/MHC complexes
and expression of co-stimulatory molecules, contributes to generation of potent antigen
specific immune responses [56].
The role of the ªlymphoidº CD123 + DC in these processes is unclear. These cells appear
to migrate from the blood via the HEVs into the T cell areas in secondary lym-
181