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

180 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination
granules [3] and dermal DCs [4, 5], which have a subtly different morphology and
phenotype. In secondary lymphoid tissues they are present as interdigitating DCs
with prominent membrane processes in the T cell area and as ªplasmacytoid monocytesº
around high endothelial venules (HEVs) [6]. Monocytes may also differentiate
directly into DC-like cells in sites of inflammation [7]. Whilst there is some uncertainty
about the identity of the different DC populations and their differentiation, it
is clear that a variety of growth factors and cytokines drive DC development [8].
Furthermore, chemokines direct their migration [9] and other soluble compounds
influence their function.
Blood DCs are commonly defined as lineage negative (Lin ± ), MHC class II positive
(MHC-II + ) cells, lacking the CD14 (monocyte), CD3 (T cell), CD19 (B cell) and CD56
[natural killer (NK) cell] lineage markers, but expressing MHC class II molecules at
high density, on their surface. They express various adhesion molecules including
CD11a (LFA-1), CD58 (LFA-3), CD54 (ICAM-1), CD50 (ICAM-3), CD102 (ICAM-2)
and CD62L (L-selectin) [1, 10]. Co-stimulatory molecules such as CD80, CD86 and
CD40 are expressed at low levels on steady-state DCs [11]. Subsets of DCs express
Fcg receptor (CD16, CD32 and CD64), complement receptors CD11c (CR4), CD11b
(CR3) and CD88 (CR5a), and lectin receptors [12, 13]. Blood DCs express high levels
of the skin homing molecule, cutaneous leukocyte antigen (CLA) [14] and L-selectin
[1,6]. Certain subsets of DC precursors circulating in the blood can express CD2,
CD14 and CD34 initially, but expression of these antigens is lost with their differentiation
into DCs [7, 15±17].
The human DC population is currently subdivided into two broad subsets based on
the reciprocal expression of the CD11 c and CD123 [interleukin (IL)-3 receptor] markers.
Myeloid CD11 c + DCs express myeloid markers (CD33 and CD13), whilst the
ªlymphoidº CD123 + DCs lack myeloid markers and express more CD4 [1, 18, 19].
Alternatively, the DC population can be subdivided into two subsets based on the expression
of immunoglobulin-like transcript (ILT) molecules. The ILT3 + /1 + subset
corresponds in the main to the CD11 c + DCs, whilst the ILT3 + /ILT1 + subset corresponds
predominantly to the CD123 + DCs [6], but further subtleties in these DC subpopulations,
particularly in CD11 c + DCs are emerging ([20] and MacDonald et al.,
submitted.
Surveillance DCs possess the unique ability to capture, process and present antigen
as peptide±MHC complexes to naive T cells and to deliver the co-stimulatory signals
necessary for T cell activation. DCs take up antigen in peripheral non-lymphoid tissues
such as skin or mucosa by pinocytosis, through the CD206 (macrophage mannose
receptor), and potentially through other lectin-like antigen uptake receptors
such as CD205 [21, 22], perhaps CD209 (DC-SIGN receptor) [23] and CD207 (Langerin)
[24]. Other molecular candidates for antigen uptake ªreceptorsº such as the
Toll-like receptors (TLRs) are now being investigated as receptors for DNA and other
microorganism-derived molecules [25].
Natural sources of antigen for DC presentation can include viral or bacterial proteins
[26, 27], apoptotic/necrotic cells [28] or exosomes [29]. DCs process antigen via the
so-called classical pathways: the endogenous antigens via the proteasome into the
MHC class Icompartment and exogenous antigens via endocytic lysosomes into the