Immune Tolerance

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Immune Tolerance

Immunological tolerance is the state of unresponsiveness towards particular antigens, whereby immune responses are prevented or suppressed. Tolerance is required to prevent:

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

T Cell Tolerance

During T cell development within the thymus, genes encoding the T cell receptor 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 too strongly to antigens expressed by the host's own tissues (autoantigens). As these cells will induce immune reactions that could be damaging to the host (Autoimmunity), they must be deleted or suppressed.

Central Tolerance

Negative selection of t cells- copyright Brian Catchpole

• Takes place within the thymus
• Involves the processes positive and negative selection
  • 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 mechanisms that induce apoptosis.

Peripheral Tolerance

It is inevitable that some self-reactive T cells will get through the thymic selection process and into the periphery, as:

• Some self-antigens are not expressed in the thymus
• Some antigens 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 is the process in which unresponsiveness towards self-antigen 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 if;

• Self-reactive T cells cannot penetrate an endothelial barrier
• Self-antigen is present in very low amount
• Self-antigen is present on cells that do not express/express low amount of MHC
• T cells are not present in sufficient numbers to mount effective response
• Self-antigen is presented without co-stimulation- can lead to ignorance or anergy, depending on type of antigen and affinity to TCR

Anergy

• Defined as a state where the T cell is still alive, but fails to respond to stimulation from its specific T cell receptor and other receptors required for activation
• Easily induced in T cells in vivo by activation of T cell receptor without co-stimulation
• Induced in vitro by injection of potent superantigens (antigens that stimulate T cells with different receptor types, using the same T cell receptor V gene)
• Can be caused by 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
• TNF via TNF receptor
• CTLA-4 recently implicated
• Subsequent signalling cascade activates proteases, such as IL-1beta Converting Enzyme (ICE), that leads to apoptosis

Immune deviation

• Th2-derived cytokines, such as IL-10, typically support antibody production, but also down-regulate macrophage effector functions, such as antigen presentation, thereby suppressing inflammatory responses
• Likewise, Th1-derived gamma-IFN can prevent Th0-Th2 differentiation
  • This process is described as immune deviation, i.e. one response being selectively induced over the other
• In the case of self-antigens, autoimmune diseases such as diabetes are caused by Th1 cells and can 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 suppress 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.