IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 14. Immunological Tolerance

PERIPHERAL, OR POST-THYMIC, TOLERANCE TO SELF-ANTIGENS

Typically, some potentially autoreactive T lymphocytes escape deletion in the Thymus and enter the peripheral lymphocyte pool. Consequently, the Blood of healthy individuals may contain autoreactive T Cells capable of reacting with self-Peptides derived from tissue-specific Antigens, such as myelin basic protein. T lymphocytes may avoid thymic deletion for several reasons:

✵ not all of the body's antigens are necessarily expressed in the thymus;

✵ not all epitopes of self-antigens possess sufficient affinity to form stable peptide-MHC molecule complexes, which is a prerequisite for T-Cell deletion;

✵ not all TCRs bind their ligands with an affinity high enough to trigger T-cell deletion.

Four mechanisms exist to prevent the autoaggressive activity of T lymphocytes that have escaped deletion:

✵ T-cell "ignorance" of self-tissular antigens;

✵ T-cell anergy;

✵ T-cell death;

✵ immune deviation or immunosuppression

Potentially autoreactive cells can "ignore" self-antigens

This phenomenon represents a passive form of tolerance to autoantigens and is observed in the following cases:

✵ if autoreactive T lymphocytes fail to cross the endothelial barrier separating cells bearing the corresponding autoantigens;

✵ if the activation of autoreactive T cells that have crossed this barrier cannot occur for any of the following reasons:

a) an insufficient amount of autoantigen for recognition;

b) insufficiency or absence of MHC molecule expression on tissue cells carrying the given autoantigen;

c) an insufficient number of T cells for an effective Immune Response;

d) absence of costimulation during antigen presentation.

T lymphocyte costimulation consists in The Cell receiving a second signal In addition to the one induced via the TCR. This additional signal enhances proliferation and stimulates T cell effector Functions, such as cytokine production and lytic activity. Costimulation can be mediated by various T cell surface molecules, although the primary role in this process belongs to the B7-CD28/CTLA-4 interaction. The CD28 molecule is expressed on the cell surface, whereas CTLA-4 is initially localized intracellularly, and its restricted surface expression depends on the ligation of the TCR. The expression of B7 On the surface of APCs is essential for the presentation of many antigens. In the absence of costimulation, antigen presentation—for example, by pancreatic cells—can lead either to the "ignorance" of autoantigens or to The Development of anergy, depending on The Nature of the antigen and the avidity of the interaction.

Anergy as a mechanism of peripheral tolerance

Cells can become unresponsive upon receiving a TCR-mediated signal. The suppression of their function can occur through the downregulation of TCR and coreceptor molecule expression. This reduction results from T cell activation and, under conditions of continuous stimulation, leads to anergy. Anergy is defined as a state in which cells remain viable but fail to perform certain functions in response to optimal stimulation mediated by both the antigen-specific receptor and other receptors required for activation. T lymphocyte anergy can be readily induced in vitro by stimulating cells via their TCR (signal 1) in the absence of costimulation (signal 2). The same result is produced by the application of antagonist peptides in the presence of signal 2. Anergy arising from the lack of a costimulatory signal is reversible; it can be overcome by stimulating T cells with IL-2. Apparently, a similar state can be reproduced in vivo by the administration of potent superantigens. However, The Significance of anergy as a mechanism of peripheral tolerance to self-antigens cannot be considered indisputable. This form of regulation is too unreliable to ensure stable tolerance to self-antigens, as there is always the danger of its reversal under METABOLISM/18.html">The Influence of cytokines, notably IL-2. Under such regulation, The Emergence of autoimmune reactions resulting from incidental inflammation or during an Immune Response to infection would be inevitable. It is possible that in many cases in vivo manifestations of tolerance attributed to the development of anergy actually reflect a state of lymphocyte paralysis preceding programmed cell death. T cell activation leading to receptor downregulation, anergy, and potentially death should be viewed as a continuous process whose outcome depends on the strength and duration of the antigenic stimulus.

Peripheral mechanism of cell death

To maintain self-tolerance and immune system Homeostasis, extrathymic T cell deletion is of great importance, whereby most T cells undergo apoptosis following antigen activation. This mechanism serves to control autoimmune reactions and maintain an optimal pool of lymphoid cells.

Peripheral T-Cell Division is initiated by the interaction of either the Fas antigen with its Ligand (FasL) or TNF with the TNF receptor. The subsequent signaling cascade activates IL-1β-converting enzyme-like proteases (ICE), which mediate programmed cell death (apoptosis). In both humans and mice, a genetically determined deficiency of Fas or Fas ligand results in a lymphoproliferative disorder. Following antigen activation of T lymphocytes, FasL expression is upregulated on the cell surface. The binding of this ligand—either in a membrane-bound or soluble form (proteolytically cleaved from the membrane)—to Fas can act as a "death signal" to neighboring T cells, triggering a process known as "fratricide" (Fig. 14.7). In certain Tissues, the Fas system serves as a defense against unwanted immune responses. For instance, testicular and retinal tissues constitutively express the Fas ligand, protecting them from the action of activated T lymphocytes.

Class="center">

Fig. 14.7. Activated T cells express both the Fas molecule (CD95) and the Fas ligand (FasL). Through either direct cell-to-cell contact or interaction with a soluble form of FasL cleaved from the membrane, "fratricide" can occur (1). Alternatively, the interaction of Fas with soluble FasL may induce cell "suicide" via an autocrine mechanism (2).

The CTLA-4 molecule also plays a crucial role as a negative regulator. Mice lacking CTLA-4 (generated via Gene knockout) develop a lymphoproliferative disorder resembling the defects seen in Fas-deficient mice, alongside widespread autoimmunity. Following antigen activation of T lymphocytes, CTLA-4 expression increases on their surface (see Fig. 11.5). The binding of this molecule to its ligand blocks CD28-dependent IL-2 production, IL-2 receptor expression, and the progression of the division cycle in activated T lymphocytes. Simultaneous ligation of the TCR and CTLA-4 triggers cell death, which can be prevented by The addition of IL-2. Thus, B7-mediated costimulation can have two distinct outcomes (Fig. 14.8):

✵ binding to CD28 leads to IL-2 synthesis, IL-2 receptor expression, and continued division of activated T cells;

✵ binding to CTLA-4 blocks CD28-dependent pathways, halts the cell division cycle, and induces cell death by suppressing IL-2 synthesis.

Fig. 14.8. The binding of B7 to CD28 generates intracellular signals that promote IL-2 production, IL-2 receptor expression, and the proliferation of activated T cells. Conversely, the binding of B7 to CTLA-4 on the cell surface blocks these CD28-dependent responses and suppresses IL-2 synthesis, inevitably leading to cell death.

Consequently, the outcome of costimulation mediated by B7 molecules on The surface of APCs is determined by the finely balanced ratio of membrane-bound CD28 and CTLA-4 expression on T cells. Studies in CTLA-4-deficient mice demonstrate that negative signaling via CTLA-4 acts as an active control mechanism against autoreactive T lymphocytes.

Immune Deviation

Peripheral tolerance to antigens can be "infectious," whereby experimentally induced tolerance to one antigen maintains tolerance or suppresses the immune response to another antigen, provided both are structurally or physically linked (e.g., localized within the same tissue). This points to a tolerance mechanism distinct from antigen "ignorance" and cell death. One proposed explanation for this form of tolerance involves two distinct T-lymphocyte populations producing different cytokines. It is well established that many inflammatory autoimmune diseases are driven by Th1 cells, which secrete IFNγ and TNFα. Conversely, cytokines produced by Th2 lymphocytes—such as IL-4, IL-5, IL-6, and IL-10—support antibody production. However, Th2-derived cytokines, particularly IL-10, also exert a vital supplementary effect by suppressing macrophage effector functions, including antigen presentation to Th1 lymphocytes and naive T cells (see Fig. 10.7). Thus, Th2 cells can downregulate inflammatory responses (including delayed-type hypersensitivity, DTH). In turn, IFNγ secreted by Th1 lymphocytes can prevent the differentiation of Th0 cells into Th2 lymphocytes. This mechanism of immune deviation was proposed over 30 years ago to explain how an Organism can mount two entirely Different types of responses to the same antigen. If guinea pigs are primed with an antigen using alum as an adjuvant, they produce high titers of IgG1 Antibodies, but no DTH develops. However, when the same antigen is administered in Freund's complete adjuvant, a robust DTH reaction ensues. It was subsequently suggested that the capacity of an antigen to elicit either a "humoral" or "cellular" immune response reflects the activation of one of two functionally antagonistic immune mechanisms. The experiments described above undoubtedly represent a form of immune deviation driven by the selective induction of Th2 rather than Th1 cells. The phenomenon of immune deviation also extends to self-antigens, as the development of T-cell-mediated disorders such as diabetes and inflammatory bowel disease can be prevented by antigen-stimulated Th2 lymphocytes.

T-Cell Tolerance Depends on the Organism's Genotype

To investigate the GENETIC BASIS OF tolerance, Transgenic Mice—in which pancreatic islet cells expressed a viral antigen, Influenza virus hemagglutinin (HA), and T cells expressed a TCR specific for this antigen (double-transgenic mice)—were crossed with mice differing in non-MHC genes (i.e., varying genetic backgrounds). In one mouse strain (BALB/c Background), HA-reactive T cells produced high levels of IL-4 and IFNγ, and these mice showed no signs of pancreatic inflammation. In contrast, HA-reactive T lymphocytes from another strain (B10.D2 background) produced exclusively Th1-type cytokines and were able to infiltrate the pancreatic islets, inducing diabetes. Clearly, immune deviation in this model is controlled by genes comprising the genetic background, many of which coordinately regulate susceptibility to autoimmune disease.