Central and Peripheral Tolerance

• The session aims to describe the mechanisms underlying central and peripheral tolerance in immune cell development
• The session outlines the in-built preventative measures that help prevent autoimmunity
• The goal is to understand and explain different forms of immune tolerance and explain some forms of autoimmunity

Before we start

• It is important to undertake immune responses carefully.
• Damaging the host is a risk because the immune system's cells have the ability to do so
• A response to self-antigens is called autoimmunity
• Autoimmune diseases are characterised by tissue damage
• Self-tolerance needs development to prevent damage
• Central tolerance occurs in developing T- and B- cells
• Peripheral tolerance is for the mature lymphocyte repertoire

Immune Tolerance

• Immune tolerance includes recognition of self and no attack on self antigens
• Negative selection (clonal deletion) results in the apoptosis of cells that react with self
• Negative selection occurs before differentiation, in B cells in bone marrow and T cells in the thymus
• Autoimmunity can occur if cells escape negative selection

Tolerance mechanisms

• Central tolerance uses the generation of T cells
• Peripheral Tolerance can cause ignorance, anergy, deletion, and suppression

Central Selection: Generation of T cells

• The bone marrow creates cells that travel to the thymus, which interacts with the heart and lungs
• Lymph nodes and the spleen interact with GALT

Maturation of T-cells steps to prevent autoimmunity

• The main events are T cell receptor gene rearrangements, positive and negative selection
• Positive selection determines can T cells interact with MHC, if not removed

Positive selection

• TCR of double positive thymocytes interact with MHC molecules on epithelial cells in thymic cortex
• Cell dies by apoptosis if no interaction
• T cell becomes "educated” to self MHC (MHC restriction) and survives if interaction

Negative selection

• Gene rearrangement produces each T-cell's receptor at random and helps T-cells to recognize “self” antigens
• Double positive T cells interact with self-peptide molecules presented on MHC by thymic dendritic cells (antigen-presenting cells)
• T cells DO NOT activate when recognising these self antigens, then they survive
• T cells bind too tightly, or activate when recognising these self-antigens, then they undergo apoptosis
• Negative selection prevents autoimmunity

Central Selection and B cells

• In the bone marrow, Naive B cells (those that have not been exposed to an antigen) have IgM as their Plasma membrane receptor
• B Cells are presented self antigens by stromal cells in the bone marrow
• The response to self antigens determines if the cell survives and continues on developing and release from the bone marrow
• Apoptosis (clonal deletion) occurs and receptor editing reprograms specificity of B cells through secondary recombination of antibody genes

Peripheral Tolerance

• The recognition of auto-antigens during central tolerance processes is limited.
• Auto-reactive immune cells can escape this process, and be released to circulate in the periphery.
• Peripheral tolerance represents another level of tolerance to prevent autoimmune issues

Peripheral tolerance: Ignorance

• Some tissues are inaccessible to immune cells, such as the brain and eyes with blood-brain-barrier protection are called "Immunoprivileged organs"
• Self-antigens sometimes ignored because they have very low rates of expression around the body
• Trauma to immunoprivileged sites can release ignored antigens into those areas, causing the immune system to launch an auto-reactive immune response, resulting in inflammation.

Peripheral Tolerance: Anergy

• Killing a T-cell that is found to be self-reactive is not always ideal during peripheral tolerance checks
• Self-reactive CD4 T-cells can be made non-responsive to an antigen via an APC improperly activated, damaged or dysfunctional
• CD4 T-cell activation: APC binds to MHC class II AND a co-receptor on the cell surface, where the T-cell's CD28 binds to B7-1 (CD80)/B7-2 (CD86)
• Example: Not-fully-activated dendritic cell might present 'self' antigen which could bind to the CD4 on a self-reactive T-cell

Action of dendritic cell

• DC activation needs necessary receptors to bind to the CD28 on the T-cell's surface
• Activation without the CD28 having bound to the co-receptor makes this T-cell anergic
• Process is reversable with cells displaying CTLA-4 on its surface competing with the CD28 for binding to B7.1 and B7.2, so the T-cell is not activated.
• Our bodies contain an altered "army" of cells which are able to react to self

Peripheral Tolerance: Suppression Regulatory T cells (T-Reg cells)

• Regulatory T-cells have a role in regulating or suppressing other cells in the immune system.
• The main classes of cells are highly-researched
• Induced T-reg cells (adaptive/peripheral T-reg cells) act as peripheral tolerance in the tissues
• Natural T-reg cells (thymic/naturally occurring T-reg cells) don’t leave the thymus.
• T-Reg cells regulate T-cell responses

T-Reg action

• T-Reg cells secrete TGF-β and IL-10 to inhibit APC’s and suppresses T-cells
• T-Reg cells detect T-cells that are responsive to self-antigens (autoreactive) and act to suppress them
• T-Reg cells use their Fas-L to interact with highly-activated T-cell’s Fas receptor to induce apoptosis.

Peripheral Tolerance: Clonal Deletion

• Activation-induced Cell Death: As T-cells are activated they start to increase expression of death receptors and can undergo apoptosis
• Fas-FasL interactions: Most effector T-cells express Fas Ligand (CD178) on their surface
• Highly activated T-cells start to also express Fas (CD95)
• Fas can come in contact with the FasL on nearby T-cells in the area
• Fas activation causes apoptosis with a death domain
• Apoptosis commences when Fas Ligand present on a cell’s surface comes in contact with Fas
• Proliferation of T-cell is terminated during an autoimmune reaction, or after a pathogen has been killed which other T-cells or T-Reg cells are nearby
• Useful for high levels of T-cells: T-cells must contact each other to engage Fas-FasL, so this serves as an additional method of peripheral tolerance and T-cell homeostasis
• Tumour cells can secrete Fas-L into the interstitial fluid around them, causing the termination of all T-cells nearby protecting the growing