THE HANDLING OF ANTIGEN
Figure 6.18 Interdigitating dendritic cells (IDCs). (a) Scanning electron micrograph of a veiled cell, the morphological form adopted by IDCs as they travel in the afferent lymph. (Source: Image courtesy of G.G. MacPherson.) (b) IDC in the thymus‐dependent area of the rat lymph node. Intimate contacts are made with the surface membranes (arrows) of the surrounding T‐lymphocytes (TL) (×2000). In contrast to these IDCs that present processed antigen to T‐cells, the follicular dendritic cells in germinal centers present intact antigen to B‐cells.
Macrophages are general antigen‐presenting cells
Antigens draining into lymphoid tissue are taken up by macrophages. The antigens are then partially, if not completely, broken down in the phagolysosomes; some may escape from the cell in a soluble form to be taken up by other APCs such as dendritic cells, and a fraction may reappear at the surface as a processed peptide associated with MHC class II. Although resting resident macrophages express very little if any MHC class II, antigens are usually encountered in the context of a microbial infectious agent that can activate the macrophage to express class II following engagement of pattern recognition receptors, such as TLR4 by bacterial lipopolysaccharide (LPS). Macrophages are also induced to express MHC class II following exposure to IFNγ or engagement of CD35 (complement receptor 1).
Interdigitating dendritic cells present antigen to naive T‐lymphocytes
Notwithstanding the
impressive ability of the mighty macrophage to present antigen, there is one
function where it is deficient, namely the priming of naive T‐lymphocytes. This is the
role of the interdigitating dendritic cell (IDC), the crème de la crème of
the APCs. Precursors in the blood enter the tissues and differentiate into
dendritic cells with phagocytic and endocytic activity. These are sometimes
described in the literature as immature dendritic cells but the reality is that
they are fully able at this stage to carry out the functions required of them,
primarily antigen detection and uptake. These cells include the Langerhans
cells in the epidermis of the skin. Receptors involved in antigen capture,
including the mannose receptor, various TLRs, and Fc receptors for both IgG and
IgE, are present on these dendritic cells. The expression of cell surface MHC
class II, and of adhesion and co‐stimulatory molecules, is low at this early stage of the dendritic cells’
life. However, as they differentiate into fully fledged APCs, they decrease
their phagocytic and endocytic activity, show reduced levels of molecules
involved in antigen capture, but dramatically increase their MHC class II. Co‐stimulatory molecules, such
as CD40, CD80 (B7.1), and CD86 (B7.2), are also upregulated. Their expression
of a number of chemokine receptors, including CCR7, CCR8, and CXCR4 (see Table
8.2) means that they are attracted to and migrate into T‐cell areas in lymphoid
tissue.
Two separate developmental
pathways for IDCs have been described: the myeloid pathway, which generates
CD11c+ interstitial myeloid dendritic cells and skin Langerhans
cells, and the lymphoid pathway, which produces plasmacytoid dendritic
cells that lack or express only very low levels of CD11 and can produce
large amounts of interferon ‐α and ‐β. There appear to be a
number of sub populations of myeloid dendritic cells, although this area is
still somewhat shaky.
In the absence of
activation, dendritic cells lack expression of co‐stimulatory molecules such as CD80 and CD86. Antigen
presented by these “tolerogenic” dendritic cells will cause T‐cell anergy or deletion owing to a lack of co‐stimulation, or will induce
regulatory T‐cells to secrete
immunosuppressive cytokines such as IL‐10 and TGFβ. Indeed, the dendritic cells themselves are also
able to secrete these cytokines. In some circumstances dendritic cells can also
exhibit a regulatory phenotype by secreting indoleamine 2,3‐dioxygenase (IDO), which
catalyzes the depletion of trytophan, in the absence of which T‐cells undergo apoptosis.
The scenario for T‐cell priming appears to be
as follows. Dendritic cells pick up and process antigen. As differentiation in
response to pattern recognition receptor stimulation proceeds, they
downregulate the adhesion molecule E‐cadherin, upregulate certain chemokine receptors including CCR7 (which
detects CCL19 and CCL21 expressed by the endothelium in peripheral lymph
nodes), and produce matrix metalloproteinases to facilitate their migration.
They then travel as “veiled” cells in the lymph (Figure 6.18a) before settling
down as IDCs in the paracortical T‐cell zone of the draining node (Figure 6.18b). There the IDC delivers the
processed protein antigen in the form of peptide–MHC together with co‐stimulatory signals (Figure
6.19) for potent stimulation of naive, and
subsequently of activated, specific T‐cells. We will meet IDCs again in Chapter 10 when wediscuss their central
role within the thymus in presenting self peptides to developing autoreactive T‐cells and triggering their apoptotic execution (known more gently as
“clonal deletion”).
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Figure 6.19 Migration of interdigitating dendritic cells (IDCs). The precursors of
the IDCs are derived from bone marrow stem cells. They travel via the blood to
nonlymphoid tissues. At this stage in their life these IDCs (e.g., Langerhans
cells in skin) are specialized for antigen uptake. Subsequently they travel via
the afferent lymphatics as veiled cells (see Figure 6.18a) to take up residence
within secondary lymphoid tissues (see Figure 6.18b) where they express high
levels of MHC class II and co‐stimulatory molecules such as B7 (CD80 and
CD86). These cells are highly specialized for the activation of naive T‐cells. The activated T‐cell may carry out its function in the lymph node
or, after imprinting with relevant homing molecules, recirculate to the
appropriate tissue.
Follicular dendritic cells bind immune complexes and stimulate B‐cells
The immunoglobulin receptors
FcγRIIB and FcεRII, together with the
complement receptors CR1 (CD35) and CR2 (CD21), on the surface of the
nonphagocytic MHC class II‐negative follicular
dendritic cells (FDCs) enables these cells to bind immune
complexes of antigen–antibody–complement very efficiently. Memory B‐cells can then be stimulated
by recognition of the antigen, and co‐stimulated through the B‐cell CD21 recognizing
complement fragments on the surface of the FDC. Intact antigens can be retained
as immune complexes on FDCs for many months or possibly even longer.
