Immune Tolerance

Immune Tolerance

Immunological tolerance occurs when there is an unresponsiveness towards particular antigens, so any further immune responses are prevented or suppressed. Tolerance is required to prevent:

• Potentially harmful inflammatory responses towards innocuous substances, such as air-borne or food molecules
• To prevent an immune attack against host tissue - this is known as self-tolerance

T Cell Tolerance

During T cell development within the thymus, genes encoding the T cell receptors are rearranged, resulting in adult cells that are able to recognise antigen fragments displayed by the host MHC molecule. Some receptors however will be self-reactive, i.e. they bind strongly to antigens expressed by the host's own tissues (autoantigens), inducing immune reactions that could be damaging to the host (autoimmune diseases); they must be deleted or suppressed.

Central Tolerance

Negative selection of t cells- copyright Brian Catchpole

Tolerance at a central level takes place within the thymus, and induces both positive and negative selections:

• During positive selection, cells passing through the thymic cortex encounter cortical epithelial cells expressing MHC molecules. Those with a suitable level of binding affinity for the MHC recieve 'survival' signals and apoptosis is prevented (at the same time cells lose either their CD4 or CD8 co-receptor)
• During negative selection, cells passing through the corticomedullary junction and thymic medulla once again encounter MHC molecules, on epithelial cells, dendritic cells and macrophages, this time bound to self-peptide. Cells bearing receptors that bind too strongly to this complex are deleted through induced apoptosis.

Peripheral Tolerance

It is inevitable that some self-reactive T cells will evade the thymic selection process and enter the peripheral circulation, because some self-antigens are not expressed in the thymus, and others will not show sufficient affinity to MHC to form the MHC:self-peptide complex required for negative selection in the thymus. Conversely some T cell receptors will not have enough affinity for their respective self-antigen to induce apoptosis. Peripheral tolerance describes an unresponsiveness towards self-antigen which is developed outside the primary lymphoid organs. There are four ways this may be achieved in T cells:

• Ignorance
• Anergy
• Cell death
• Immune deviation/suppression

Ignorance can occur when self-reactive T cells cannot penetrate an endothelial barrier, when self-antigen is present in very low amounts, when self-antigen is present on cells that do not express or express low amounts of MHC or when self-antigen is presented without co-stimulation, which can lead to ignorance or anergy, depending on the type of antigen and the affinity to the TCR. Ignorance also occurs when the T cells are not present in sufficient numbers to mount an effective response.

Anergy is defined as a state where the T cell is still alive, but they fail to respond to stimulation from its specific T cell receptor and other receptors are required for activation. Anergy is easily induced in T cells in vivo by activation of T cell receptors without co-stimulation; it can be induced in vitro by the injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene). Anergy occurs naturally when there is a downregulation of T cell receptors as a result of chronic stimulation. Anergy induced without co-stimulation can be reversed by IL-2.

Cell death; Peripheral deletion of T cells requires the engagement of Fas by Fas ligand. Deficiencies in Fas ligand lead to lymphoproliferative disorders. After activation by an antigen, T cells upregulate expression of Fas ligand - some tissues, such as the testis and retina, constitutively express Fas ligand to protect themselves from activated T cells

Cell death is also induced by TNF via the TNF receptor; CTLA-4 has recently also been implicated in cell death. The subsequent signalling cascade activates proteases, such as IL-1beta Converting Enzyme (ICE), that leads to cell apoptosis.

Immune deviationcan be described as one immune response being selectively induced over another potential response - examples include Th2-derived cytokines, such as IL-10, which typically support antibody production, but can also down-regulate macrophage effector functions, such as antigen presentation, thereby suppressing the inflammatory response. Likewise, Th1-derived gamma-IFN can prevent Th0-Th2 differentiation. In the case of self-antigens, autoimmune diseases such as diabetes which are caused by Th1 cells can theoretically be prevented by 'antigen-primed' Th2 cells.

Mucosal tolerance

Mucosal tolerance is the systemic unresponsiveness towards antigens administered across the mucosal surfaces

• As the highest antigenic load of the body surfaces occurs in the GI tract, it is also known as oral tolerance
• When oral tolerance towards food antigens breaks down, inflammatory autoimmune responses are induced
• Gut associated lymphoid tissue is important for developing oral tolerance:
  • Animals that lack Peyer’s patches and mesenteric lymph nodes do not develop oral tolerance
  • It is thought the liver and spleen may also play a role

Mechanisms

• High doses of antigen can cause anergy or cell death
• Low doses can induce a T cell response:
  • The antigen is taken up and presented, inducing a Th2-like cell response
  • This cell response produces cytokines that suppress the Th1 inflammatory response, such as IL-10 and TGF-beta
    • Although the cellular response is antigen-specific, the cytokines released are not. TGF-beta is known to inhibit the proliferation and function of B-cells, cytotoxic T cells and NK cells. This means tolerance induction to one antigen suppresses an immune response to a second associated antigen- this mechanism has been used to suppress some autoimmune diseases by feeding with an antigen isolated from the affected tissue. This is known as ‘’bystander suppression’’.

Other mucosal surfaces

• Nasal deposition of some peptides can be used to induce tolerance, controlling both humoral and cellular responses
• Administration of antigen in aerosol form to the lung has been used to control both allergic and autoimmune responses

Regulatory T Cells

A number of cell populations identified during studies on autoimmunity and organ transplantation have shown the capacity to suppress responses to self-antigen and regulate rejection. Although once considered a tentative theory, this form of tolerance is now considered a major mechanism in the protection of host tissue from immune attack.

Regulatory T cells- copyright Brian Catchpole

• Known as regulatory T cells, these CD4+ cells are antigen-specific
• Currently thought to develop in the thymus
• They usually release inhibitory cytokines, e.g. IL-4, IL-10 and TGF-beta
• When their TCRs bind to an antigen, they do not proliferate themselves but suppress the proliferation of other naive T cells responding to that antigen
• Mechanism of suppression is dependent on:
  • CTLA-4 on the regulatory T cell binding with B7 on the target T cell
• Both cells binding the same antigen
• Regulatory T cells are unique in their use of a transcription repressor known as FoxP3
  • Encoded by a gene on the X chromosome, rare deficiencies in FoxP3 are characterised by autoimmunity, primarily towards gut tissue, the thyroid, pancreative beta-cells and the skin. Sufferers are unable to produce regulatory T cells and the only known treatment is a bone marrow transplant from a MHC-identical sibling.