Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance

Abstract

The immune system generally avoids horror autotoxicus or autoimmunity, an attack against the body's own constituents. This avoidance requires that self-reactive T cells be actively silenced or tolerized. We propose that dendritic cells (DCs) play a critical role in establishing tolerance, especially in the periphery, after functioning T cells have been produced in the thymus. In the steady state, meaning in the absence of acute infection and inflammation, DCs are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. Nevertheless, immature DCs continuously circulate through tissues and into lymphoid organs, capturing self antigens as well as innocuous environmental proteins. Recent experiments have provided direct evidence that antigen-loaded immature DCs silence T cells either by deleting them or by expanding regulatory T cells. This capacity of DCs to induce peripheral tolerance can work in two opposing ways in the context of infection. In acute infection, a beneficial effect should occur. The immune system would overcome the risk of developing autoimmunity and chronic inflammation if, before infection, tolerance were induced to innocuous environmental proteins as well as self antigens captured from dying infected cells. For chronic or persistent pathogens, a second but dire potential could take place. Continuous presentation of a pathogen by immature DCs, HIV-1 for example, may lead to tolerance and active evasion of protective immunity. The function of DCs in defining immunologic self provides a new focus for the study of autoimmunity and chronic immune-based diseases.

Figure 1

Central and peripheral mechanisms for avoiding horror autotoxicus via T lymphocytes. In the thymus (central tolerance) and in other parts of the body (peripheral tolerance), self-reactive T cells can either be eliminated (deleted) or regulated (suppressed) by other T cells. Several types of antigen-presenting cells can bring about tolerance as shown by the arrows. DCs play a pervasive role, particularly for dying cells and innocuous self and environmental proteins that have to be captured and processed before presentation (as MHC class I and II–peptide complexes) to antigen receptors on T cells.

Figure 2

DC maturation, a control point for regulating tolerance and immunity. Immature DCs capture antigens by several pathways, whereas mature DCs stimulate T cell immunity, i.e., helper and cytolytic effector lymphocytes as well as memory. Maturation stimuli act via TLRs (wherein distinct microbial products act although distinct TLR) and TNF family receptors (such as TNF itself and CD40L). Maturation leads to several changes, including: the redistribution of MHC class II molecules and MHC–peptide complexes from within the endocytic system to the cell surface as diagrammed here, the production of several cytokines and membrane associated T cell stimulatory molecules, and the remodeling of expressed chemokine receptors.

Figure 3

Overcoming the risk of autoimmunity and horror autotoxicus inherent to the maturation of DCs on exposure to pathogens. During infection, DCs mature, e.g., in response to pathogen signals via TLRs (Fig. 2). However, the maturing DCs will likely be presenting peptides not only from the pathogen but also from dying self tissue and innocuous environmental proteins. To overcome this risk, it is proposed that immature DCs induce antigen-specific peripheral tolerance in the steady state, before DC maturation during inflammation and infection. DCs can do so by deleting naïve T cells or inducing regulatory T cells. The tolerized T cells can either be self-reactive lymphocytes that have escaped central tolerance or T cells reactive to innocuous proteins in the environment.

Figure 4

Potential sites for involvement of DCs in HIV pathogenesis. In the virologic pathway (Upper), emphasized in the past, DCs catalyze HIV replication in T cells. In the immunologic pathway (Lower) proposed here, immature DCs continually capture and even replicate HIV virions, which induces peripheral tolerance, including regulatory T cells, thereby blocking the effector or protective limbs of the immune response.