Mechanisms of Peripheral Tolerance

One mechanism of peripheral tolerance may be deletion, too. Deletion is mainly associated with the sudden appearance of a large number of antigens. This mechanism has been demonstrated for antigens that were presented in large numbers, thus during infection or following injection of superantigens

Negative Positive Negative

Fig. 1. Modes of intrathymic selection of T cells. T cells with a very high affinity T cell receptor (TCR) for self major histocompatibility complexes (MHC) die from active deletion, those with an intermediate affinity are positively selected and those with low affinity will die from neglect

Fig. 1. Modes of intrathymic selection of T cells. T cells with a very high affinity T cell receptor (TCR) for self major histocompatibility complexes (MHC) die from active deletion, those with an intermediate affinity are positively selected and those with low affinity will die from neglect

(Moskophidis et al. 1993; Webb et al. 1990). Whether this mechanism applies also under physiological conditions is not clear. But it may become relevant during tissue destruction, when large quantities of self-antigens are presented, thus in the case of skin burning, viral infections of skin, muscle or other organs or following a stroke. However, this phenomenon has not yet been analyzed in more detail.

Another mechanism is suppression of TCR expression. This has been shown with pregnant mice expressing a transgenic TCR that recognizes the foreign MHC class I molecule expressed by the father and the fetus. The level of this transgenic TCR is high before and after pregnancy, but low during pregnancy. These T cells are also functionally silenced. During pregnancy, female mice become even tolerant to otherwise highly immunogenic tumor cells expressing this same antigen (Alferink et al. 1998). Thus, suppression of a TCR expression is closely associated with the occurrence of peripheral tolerance and may contribute to it. These data, even though very elegant, do not exclude that other mechanisms significantly contribute to peripheral tolerance (Alferink et al. 1998; Schonrich et al. 1991).

One important example demonstrating the requirement for additional mechanisms was given by mice that simultaneously express a peptide antigen of the lymphocytic choriomeningitis virus (LCMV) by the endocrine pancreas and T cells with a TCR transgenic for the LCMV peptide (Ohashi et al. 1991; Oldstone et al. 1991). These animals have autoreactive CD8+ T cells that are functionally normal, express normal levels of the TCR and kill peptide loaded targets in vitro to the same extend as transgenic T cells from control animals. Nevertheless, these animals do not develop overt autoimmune disease, showing that, besides the target organ, the expression of an endogenous potentially immunogenic peptide and normal levels of TCR, other signals are required for the induction of autoimmune disease. Such a situation may be the consequence of 'ignorance' of the target structure by the autoreactive T cells (Ohashi et al. 1991). Ignorance may be the consequence of missing adhesion molecules or the absence of co-stimulatory signals (von Herrath et al. 1995). However, it may also be due to expression of autoantigens at immunologi-cally privileged sites, the expression of apoptosis inducing molecules capable of killing activated T cells or secondary to local silencing of activated T cells that recognize target tissues in the absence of co-stimulatory molecules.

Reactivity and mode of action are not only given by the TCR and the spectrum of co-stimulatory T cells expressed by T cells. Most importantly, T cell functions are determined by the cytokines they produce. Naive T cells produce only interleukin (IL-) 2 when stimulated by peptides and professional antigen presenting cells (APC; (Weinberg et al. 1990). Subsequently, T cells develop towards memory cells that are theoretically capable of producing a large spectrum of cytokines. Today it is established that T cells normally do not secrete a random pattern of cytokines, but differentiate into phenotypes that produce distinct sets of cytokines associated with well defined functional phenotypes (Mosmann and Sad 1996; Rocken et al. 1992; Rocken et al. 1996).

T cells that produce predominantly IL-2 and interferon-y (IFNy) are associated with inflammatory, cell mediated immune responses. When expressing the CD4 molecule they are named Th1, when expressing the CD8 molecule, they are named Tc1 cells and induce 'type 1' immune responses (Arnold et al. 1993; Racke et al. 1994; Katz et al. 1995; Kolb et al. 1995; Powrie 1995; Rocken et al. 1996; Adorini and Sinigaglia 1997). These types of immune responses are required for the control of infections with viruses, funghi or parasites. However, when directed against autoantigens, they may cause inflammatory autoimmune diseases. These inflammatory autoimmune diseases are normally well localized to one single organ or a group of organs that share a common antigen. These T cells do not only induce direct tissue destruction, they also induce B cells to produce complement binding antibodies, which may enhance local inflammation and tissue destruction, as it is the case in patients with bullous pemphigoid (Budinger et al. 1998).

The most important counterpart of 'type 1' immune responses are 'type 2' responses. They are induced by CD4+ T cells capable of producing IL-4 and IL-13. These two cytokines seem to suppress multiple pro-inflammatory effector functions by macrophages, such as production of tumor necrosis factor (TNF). Th2 cells are primarily known by their capacity to switch the immunoglobu-lin isotype of human B cells towards IgE and probably also IgG4 (Mosmann and Coffman 1989). Thus, Th2 cells do not generally extinct immune responses. They may even induce autoimmune responses and probably also autoimmune disease, such as pemphigus vulgaris, which is associated with autoantibodies of the IgG4 isotype and little local inflammation (Goldman et al. 1991; Hertl et al. 1998). However, when directed against epitopes that are associated with type 1-mediated inflammatory autoimmune disease, type 2 immune responses may exert anti-inflammatory, protective effects. Treating Th1 mediated diseases with Th2 cells or the cytokine IL-4 that most potently induces Th2 and suppresses Th1 has been demonstrated in animal models of organ specific autoimmune disease and skin inflammation. Most importantly, however, this therapeutic strategy was also effective in humans suffering from psoriasis, a Th1 mediated autoimmune disease of the skin (Ghoreschi et al. 2003).

A third, probably increasingly important population are IL-10 producing regulatory or Tr cells. In contrast to all other phenotypes, these Tr cells seem to have the exquisite capacity of turning immune responses off. This regulatory effect may be of great importance in the treatment of autoimmune diseases, since Tr are obviously capable of silencing both, type 1 and type 2 immune responses (Groux et al. 1997; Akdis et al. 2000). Referring to the historical attribution given to CD8+ T cells, suppressor T cells experience a time of renaissance. These CD4+ T cells are capable to suppress autoaggressive immune reactions and were found to express CD25, GITR, CTLA-4, and most importantly a specific transcription factor, forkhead box p3 (Foxp3) (Bluestone and Tang 2004). Foxp3 is not only a marker for these Tr, it is of functional importance for the suppressive mode of action of Tr (Walker et al. 2003; Fontenot et al. 2003). As a consequence, patients deficient in the Foxp3 transcription factor develop a multiorgan autoimmune disease (Kriegel et al. 2004). Tr cells are very difficult to induce and grow to expand in vitro and probably also in vivo, but finding Foxp3 and increasingly elucidating the underlaying mechanisms of Tr development will help to answer the questions in regard to the significance these cells may play in the therapy of autoimmune disease.

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