Induction o f tolerance by DCs

For a long time, much attention has been focussed on the exceptional ability o f DCs to

elicit T and B cell responses, and their potential as therapeutic immunological

adjuvants. However, there is accumulating evidence suggesting that antigen

So far, the conventional view o f DC function has been that DCs in the periphery pick

up antigens and migrate into the T cell areas upon maturation, thereby initiating an

antigen-specific immune response. The function o f resident lymphoid DCs was

considered to be separate from that o f migratory DCs, in that DCs that reside in the T

cell areas o f lymphoid organs function as inducers o f tolerance to self antigens

(Steinman et al., 1997). The latter idea is based on the observation that in mice, DCs

within T cell areas express high levels o f self-antigens and functional Fas-L capable

o f inducing CD4^ T cell death (Suss and Shortman, 1996). However, if migratory

myeloid DCs function solely to bring in antigens from the periphery and induce

immunity, and resident lymphoid DCs only to present self-antigens and maintain self­

tolerance (Steinman et a l, 1997), the question arises: how do the lymphoid DCs

acquire self antigens from the periphery, if these cells are not capable o f migration?

In addition, a different, but related question is, given that immature DCs are

disseminated throughout the peripheral tissues and capture antigen from dying cells

during the turnover o f normal tissue, how are DCs prevented from inducing an

immune response against self antigen? This question m ay partly be answered by data

showing that freshly isolated DCs from lymphoid organs are functionally immature

(Mellman and Steinman, 2001). However, these DCs from lymphoid tissues present

large amounts o f MHC products and MHC-peptide complexes on their surface in vivo

(Inaba et al., 1998), which contrasts with the features o f immature DCs in vitro.

These “immature” DCs found in lymphoid organs are endocytically active and

express relatively low levels o f key costimulatory molecules such as CD86 and CD40

In addition, an old observation suggests that, even in the absence o f overt stimuli,

DCs traffic from tissue parenchyma to lymph nodes (Kelly et al., 1978). This was

further supported by recent studies that DCs capture antigens against which immunity

is normally avoided. For example, DCs that line the airways transport soluble

macromolecules from the airway to the lymph nodes in the chest (Vermaelen et al.,

2001). DCs in intestinal lymphatics were also shown to capture constitutively

proteins placed in the gut lumen and fragments o f apoptotic epithelial cells and carry

the antigens to the T cell area o f mesenteric lymph nodes (Huang et al., 2000). In

these cases, if DCs were to be immunogenic, chronic inflammation would ensue.

These observations suggest that even in the absence o f infection, DCs are constantly

sampling the periphery and are migrating to the secondary lymphoid organs in an

“immature” form, thus preventing T cell activation to self antigens captured in the

periphery. This contradicts the paradigm set out earlier that DCs only migrate to

draining lymph nodes when they have captured nonself antigen in the context o f

inflammatory stimuli.

So how do DCs achieve two contrasting roles: induction o f immunity and tolerance?

Recently, it was shown that DCs respond differently to damaged cells, depending on

how they die; necrotic cells promote the maturation o f DCs and strong CD4^ and

CD8^ T cell stimulatory activity, whereas apoptotic cells fail to activate DCs

(Gallucci et al., 1999; Sauter et al., 2000). Thus, in the absence o f ‘danger’ signals

DCs may be constantly inducing peripheral tolerance to self antigens acquired during

i.e., in the absence o f microbial or other perturbations, allows DCs to control

tolerance to self and normal environmental constituents.

One mechanism that might be used by DCs to maintain self tolerance is the

presentation o f exogenous (primarily cell-derived) antigens to CD8^ T cells (cross

presentation) or CD4^ Tb cells, which may be mediated by presentation o f antigens

derived from apoptotic cell fragments by DCs (Albert et al., 1998). fri support o f this,

Kurts et al demonstrated that in OVA-expressing transgenic mice, OVA-specifrc

CD8^ T cells were rendered tolerant upon encounter with bone marrow-derived APCs

in the lymph nodes draining the sites o f OVA expression (Kurts et al., 1996; Kurts et

al., 1998; Kurts et al., 1997).

Taken together, migratory DCs could have either T cell stimulatory function induced

by danger signals, or tolerising function if they have captured antigen in the absence

o f danger signals. A recent study by Hawiger et al (Hawiger et al., 2001)

demonstrated that in the absence o f danger signals DCs in vivo are indeed capable o f

migrating and carrying antigen captured in the periphery, and subsequently inducing

tolerance o f responding T cells. Therefore, it is likely that even within one lineage

(not necessarily the lymphoid lineage) DCs do not only function as T cell stimulators,

but in the absence o f infection or ‘danger’ they migrate to lymphoid organs in an

immature state, presenting self-antigen captured in the periphery, thereby maintaining