Immune Cell Development: Mechanisms Underlying Tolerance - Lecture Notes PDF

Immune cell development: Mechanisms underlying central and peripheral tolerance Associate Professor Christian Moro This session  Once a microbe or pathogen breaches the skin, or enters our body, the immune system has a variety of defence systems to help neutralise the infections and clea...

Immune cell development: Mechanisms underlying central and peripheral tolerance Associate Professor Christian Moro This session  Once a microbe or pathogen breaches the skin, or enters our body, the immune system has a variety of defence systems to help neutralise the infections and clear the threat.  However, sometimes it goes wrong. Autoimmunity can result in a compromised immune system, allergies, or serious damage to the internal cells and tissues.  In this session, we’ll outline the in-built preventative measures that help prevent this from occurring. Session aims:  Understand and explain the different forms of immune tolerance  Explain some forms of autoimmunity Before we start Immune responses must be undertaken carefully the immune system’s cells have the ability to damage the host. A response to self-antigens is called autoimmunity. Autoimmune diseases are characterised by tissue damage. We need to develop self-tolerance, so this does not occur Central tolerance (developing T- and B- cells) Peripheral tolerance (for the mature lymphocyte repertoire) Image source: https://invisiverse.wonderhowto.com/news/unusual-stomach-survival-mechanisms-ulcer-causing-bacteria- could-be-its-achilles-heel-0175622/ Immune Tolerance  Recognition of self  No attack on self antigens  Negative selection (clonal deletion)  Before differentiation  B cells in bone marrow  T cells in thymus  Cells which react with self are destroyed (via apoptosis)  Autoimmunity  Cells which escape negative selection Photo by  Tolerance Mechanisms: F CE EL N S RA LE TO  Central Tolerance  Peripheral Tolerance Ignorance Anergy Deletion Suppression Central Selection: Generation of T cells 1 2 Maturation of T-cells: steps to prevent autoimmunity Main events: Positive selection - T cell receptor gene rearrangements TCR of double positive thymocytes interact with MHC - Positive selection (can T cells interact with MHC? If not, these are removed) molecules on epithelial cells in thymic cortex - Negative selection (T cells with affinity to self antigens will be removed)  If no interaction cell dies by apoptosis  If interaction: T cell becomes “educated” to self MHC (MHC restriction) and survives Negative selection As the gene rearrangement to produce each T-cell’s receptor is random; T-cells that recognize “self” antigens can occur. +  Double positive T cells interact with (self) peptide molecules presented on MHC by thymic dendritic cells (antigen-presenting cells) - * If T cells DO NOT activate when recognising these self antigens, then they survive * If T cells bind too tightly, or activate when recognising these self antigens, then they undergo apoptosis Negative selection prevents autoimmunity Central Selection: 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. Or: Apoptosis (clonal deletion) or Receptor editing, which reprogrammes the specificity of B cells through secondary recombination of antibody genes Other tolerance mechanism (anergy etc). More info in the link to the right (not required reading). NOT required reading, but if you wish to dive a bit deeper into B-cell central tolerance, two helpful articles are: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623591/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312675/ Peripheral Tolerance  The recognition of auto-antigens during central tolerance processes is limited  Some auto-reactive immune cells can escape this process, and be released to circulate in the periphery  As such, there is a need for another level of tolerance: peripheral tolerance Photo by CDC Peripheral tolerance: Ignorance Ignorance: - Some tissues are inaccessible to immune cells: e.g. Brain and eyes (protection from the blood-brain-barrier). These are often referred to as “Immunoprivileged organs” - In some cases, self-antigens have very low rates of expression around the body and can simply be ignored. Note regarding immunoprivileged sites: In the case of trauma, antigens that had been previously ignored by the immune system could be released into these areas. Immune cells might then launch an auto-reactive immune response. Severe inflammation can result. Brain illustration by Christian Moro  Peripheral Tolerance: Anergy During peripheral tolerance checks, simply killing a T-cell that is found to be self-reactive to a specific antigen may not always be ideal. Instead, some self-reactive CD4 T-cells can be made non-responsive to an antigen by non- professional APC’s. Usually, a CD4 T-cell is activated by an APC, where it binds to MHC class II AND, a co- receptor on the cell surface [in the image the T-cell’s CD28 binds to B7-1 (CD80)/B7-2 (CD86)]. Example: a not-fully-activated dendritic cell might present ‘self’ antigen, which could bind to the CD4 on a self-reactive T-cell. However, as the DC isn’t fully activated, it wouldn’t also express the necessary receptors to bind to the CD28 on this T-cell’s surface. Activation without the CD28 also having bound to the co-receptor, causes this T-cell to become anergic. The process is reversable. The anergy commonly occurs by the T-cell displaying CTLA-4 on its surface, which outcompetes with the CD28 for binding to B7.1 and B7.2, so this T- cell can’t become activated. This means that our bodies contain a small army of cells which can react to self, but have been altered so they do not. Peripheral Tolerance: Suppression Regulatory T cells (T-Reg cells) 1. Regulatory T-cells have a role in regulating or suppressing other cells in the immune system. 2. Still remain a highly-researched cell. Currently, the main classes are:  Induced T-reg cells (also called adaptive/peripheral T-reg cells) which act as peripheral tolerance in the tissues  Natural T-reg cells (also called thymic/naturally occurring T-reg cells) which don’t leave the thymus. 3. T-Reg cells work to regulate T-cell responses by:  Secreting TGF-β and IL-10, which inhibits APC’s and suppresses T-cells.  Detecting T-cells that are responsive to self-antigens (autoreactive) and acting to suppress them.  Most likely other ways which haven’t been discovered or fully clarified yet.  Using their Fas-L to interact with highly-activated T-cell’s Fas receptor to induce apoptosis (the next slide Links to disease: Defective T-Reg cells have been associated (mainly in mice) with a range of autoimmune diseases, such asthma, diabetes, multiple sclerosis and some cancers (a developing area of research). As such, T-Reg cells may have a therapeutic potential for treatment of autoimmune diseases if we could isolate them and infuse into patients. Other cells? There are other specialized T-Reg cells that act in a regulatory capacity but do not express a protein called FoxP3 (primarily acting through IL-10). These have been observed in the intestinal systems in mice, but more research still needs to be done before the role of these T-Reg cells is clarified. Images: Janeway’s Immunobiology, 8th Edition, Garland Science, 2012. Peripheral Tolerance: Clonal Deletion Activation-induced Cell Death. As T-cells are activated they start to increase their expression of death receptors and other means to eventually undergo apoptosis. Example: Fas-FasL. 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 (CD95) has a “death domain” and its activation causes apoptosis.  Fas can come in contact with the FasL on nearby T-cells in the area.  When the Fas Ligand present on a cell’s surface comes in contact with Fas, apoptosis commences.  This helps terminate T-cell proliferation during an autoimmune reaction, or after a pathogen has been killed, as there are usually other T-cells or T-Reg cells nearby. Image: Janeway’s Immunobiology, 8th Edition,  As the T-cells need to come in contact with each other to engage Fas-FasL this system is particularly useful when T-cells are Garland Science, 2012. present in high numbers. This acts as an additional method of peripheral tolerance and T-cell homeostasis. *interesting fact: Some tumour cells have been observed secreting Fas-L into the interstitial fluid around them. This would terminate any T-cells nearby and hence protect the growing cancer from immunological attack! Relevant additional videos on Immunology Why do you get a fever when you’re sick? (one of Christian’s Ted-Ed videos) What are the benefits of a fever? Why does the skin scar? What is shock?