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peripheral tolerance

Tuesday 10 March 2009

Peripheral tolerance. Those self-reactive T cells that escape intrathymic negative selection can inflict tissue injury unless they are deleted or muzzled in the peripheral tissues. Several "back-up" mechanisms that silence such potentially autoreactive T cells are known to exist.

They include the following:

- Anergy

Anergy refers to prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions. Activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on the surface of antigen-presenting cells and a set of costimulatory signals ("second signals") provided by antigen-presenting cells.

To initiate second signals, certain T cell-associated molecules, such as CD28, must bind to their ligands (the costimulators B7-1 and B7-2) on antigen-presenting cells. If the antigen is presented by cells that do not bear the costimulators, a negative signal is delivered, and the cell becomes anergic.

Once lymphocytes become anergic, they cannot be activated even if the relevant antigen is presented by competent antigen-presenting cells (e.g., dendritic cells) that can deliver costimulation.

Because costimulatory molecules are not expressed or are weakly expressed on most normal tissues, the encounter between autoreactive T cells and their specific self-antigens may lead to anergy.

In some situations, T cells that recognize self-antigens receive an inhibitory signal from a receptor called CTLA-4 that also binds to B7 molecules. Mice in which the gene for CTLA-4 is knocked out develop massive lymphproliferation and fatal multisystem autoimmune disease with T-cell infiltrates in tissues.

Polymorphisms in the CTLA-4 gene are associated with some autoimmune endocrine diseases in humans.

How T cells choose to use CD28 to recognize B7 molecules and be activated or CTLA-4 to recognize the same B7 molecules and become anergic is an intriguing question to which there are no clear answers. Anergy affects B cells in the tissues as well.

It is believed that if B cells encounter antigen in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation, and may be excluded from lymphoid follicles.

Suppression by regulatory T cells: Recent evidence, mostly from experiments in mice, has emphasized the role of a population of T cells called regulatory T cells in preventing immune reactions against self-antigens.43 Regulatory T cells may develop in the thymus, as a result of recognition of self-antigens, or they may be induced in the periphery.

The best-defined regulatory T cells are CD4+ cells that constitutively express CD25, the α chain of the IL-2 receptor, but some CD4+ cells lacking CD25 may serve the same function.

The mechanisms by which these regulatory cells suppress immune responses are not fully defined. There is some evidence that peripheral suppression of autoreactivity may be mediated, in part, by the secretion of cytokines, such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions.

A transcription factor of the forkhead family, called Foxp3, is required for the development and function of CD4+ CD25+ regulatory T cells.44 Mutations in Foxp3 result in severe autoimmunity in humans and mice; in humans, these mutations are the cause of an autoimmune disease called IPEX (for Immune dysregulation, P olyendocrinopathy, Enteropathy, X-linked).

- Clonal deletion by activation-induced cell death

CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis. This process has been called activation-induced cell death, because it is a consequence of T-cell activation. One mechanism of activation-induced death of CD4+ T cells involves the Fas-Fas ligand system.

Lymphocytes as well as many other cells express Fas (CD95), a member of the TNF-receptor family. FasL, a membrane protein that is structurally homologous to the cytokine TNF, is expressed mainly on activated T lymphocytes. The engagement of Fas by FasL induces apoptosis of activated T cells and may underlie the peripheral deletion of autoreactive T cells.

It is believed that those self-antigens that are abundant in peripheral tissues cause repeated and persistent stimulation of self-antigen-specific T cells, leading eventually to their elimination via Fas-mediated apoptosis.

Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells. The importance of this mechanism in the peripheral deletion of autoreactive lymphocytes is highlighted by two strains of mice that are natural "knockouts" of Fas or FasL.

The so-called lpr mice have a mutation in the Fas gene, whereas the gld mice are born with defective FasL. Mice of both of these strains develop severe autoimmune disease resembling human SLE. (In contrast to SLE, however, these mice also suffer from generalized lymphoproliferation.)

A small number of patients have also been identified with SLE-like autoimmunity and generalized lymphoproliferation associated with mutations in the FAS gene; this disease is called the autoimmune lymphoproliferative syndrome.

Recently, another mechanism of activation-induced cell death has been proposed, again based on studies in mice.

It is postulated that if T cells recognize self-antigens, they may express a pro-apototic member of the BCL family, called BIM, and this protein inhibits the function of anti-apoptotic members of the family. The importance of this mechanism of cell death in self-tolerance is not established.

- Antigen sequestration

Some antigens are hidden from the immune system because the tissues in which these antigens are located do not communicate with the blood and lymph.

This is believed to be the case for the testis, eye, and brain, all of which are also called immune-privileged sites because it is difficult to induce immune responses to antigens in these sites.

If the antigens of these tissues are released, for example, as a consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis.