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- 2. UNDERSTANDING CELL-MEDIATED IMMUNITY AND DISEASES Dr. Keibren Robinson PG-Y1 DM Internal Medicine Moderator: Dr. K. Hoe, Nephrologist
- 3. OUTLINE • Overview of the Immune System • Cell-mediated Immunity • T-cells • Cell-mediated Hypersensitivity • Superantigens • Autoimmune Diseases • T-cell-mediated Diseases • Type 1 Diabetes • Rheumatoid Arthritis • Multiple Sclerosis • Systemic Sclerosis (Scleroderma) • Transplant Rejection 3
- 4. ROLE OF THE IMMUNE SYSTEM Abbas, A. K., Lichtman, A. H., & Pillai, S. (2016). Basic Immunology: Functions and Disorders of the Immune System. 4
- 5. CATEGORIES OF IMMUNITY 1. Innate (native) immunity a. It is nonspecific and present from birth. b. Encompasses protective factors present in an individual independent of antigenic stimulus. c. It is an initial, rapid recognition system for detection of pathogens. 2. Adaptive (acquired) immunity a. It is specific. Humoral vs. Cell-mediated Immunity. b. It is acquired actively by infection or vaccination. c. It is acquired passively by placental transfer or injection of specific antibody. 5
- 6. ADAPTIVE (ACQUIRED) IMMUNITY 1.Humoral Immunity a. Mediated by antibodies. b. Neutralizes microorganisms and toxins. c. Removes antigens in the body fluids by amplifying phagocytosis or lysis by complement. 2.★Cell-mediated Immunity★ a. Mediated mainly by T-cytotoxic cells, Natural Killer (NK) cells and activated macrophages. b. Responsible for eradicating microorganisms residing within body cells. 6
- 7. ADAPTIVE (ACQUIRED) IMMUNITY Abbas, A. K., Lichtman, A. H., & Pillai, S. (2016). Basic Immunology: Functions and Disorders of the Immune System. 7
- 8. CELL-MEDIATED IMMUNITY PROTECTS THE BODY BY: 1. Activating antigen-specific cytotoxic T-lymphocytes (CTLs). 2. Activating macrophages and NK cells. 3. Stimulating cells to secrete a variety of cytokines. 8
- 9. ORGANS INVOLVED IN CELL-MEDIATED IMMUNITY 1.Central lymphoid organs a. Immunocompetent cells develop here. b. Comprised of the thymus, bone marrow and fetal liver. 2.Peripheral lymphoid organs a. Immunocompetency is expressed here. b. Includes the spleen, lymph nodes, tonsils, and intestinal Peyer’s patches. 9
- 10. CELLS INVOLVED IN CELL-MEDIATED IMMUNITY 1.T Lymphocytes a. Helper T Lymphocyte (TH cell) b. Cytotoxic T Lymphocyte (TC cell) 2. Natural Killer (NK) Cells 3. Activated Macrophages 10
- 11. T-CELL DEVELOPMENT T-cells originate from lymphoid progenitor cells in the bone marrow and mature in the thymus. • Positive selection of T-cells • Ensures that the thymus produces functional T- cells. • Location: thymic cortex. • Negative Selection of T-cells • Ensures that the thymus does not produce self- reacting T-cells. 11
- 12. T-CELL RECEPTORS (TCRS) • Complex of proteins of the immunoglobulin superfamily. • Each T-cell expresses a TCR variant that binds to one specific antigen. • The antigen fragment has to be presented by a major histocompatibility complex (MHC) molecule of an antigen-presenting cell in order to be recognized by the TCR. • Important for positive and negative selection during T-cell development. 12
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- 14. TCR COMPARED TO IMMUNOGLOBULINS Similarities • Both have a specific antigen-binding region created by the variable regions of two polypeptide chains. • Both display great potential for diversity via genetic recombination at the genome level. Differences • A TCR is monovalent. An immunoglobulin is bivalent. • The TCR has no secreted form. It is always membrane-bound. • The TCR does not recognize free antigen. Antigen must be presented to a T cell on an MHC molecule. • There is no class switching for the TCR. Once made, the TCR does not change. 14
- 15. T-CELLS AND MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • TCRs only recognize antigens combined with MHC proteins on the surface of cells. • MHC Class I: Found on all cells. • MHC Class II: Found on phagocytes. • Clonal selection increases number of T cells recognizing a specific antigen. 15
- 16. T-CELLS AND CELL-MEDIATED IMMUNITY 16
- 17. T-HELPER (TH) CELLS • Central role in immune response. • They are CD4+ (TH1 or TH2) • Recognize antigen associated with MHCII on the surface of antigen presenting cells. • Induce formation of cytotoxic T-cells • TH1 activates macrophages. • TH2 stimulates B-cells to produce antibodies. 17
- 18. T-CYTOTOXIC (TC) CELLS • Destroy target cells. • They are CD8+ (and CD4-). • Recognize antigens associated with MHC I on the surface of all cells: • Kill host cells that are infected with viruses or bacteria. • Recognize and kill cancer cells. • Recognize and destroy transplanted tissue. • Release protein called perforin which forms a pore in target cell, causing lysis of infected cells. • Undergo apoptosis when stimulating antigen is gone. 18
- 19. CYTOTOXIC T-CELLS LYSE INFECTED CELLS 19
- 21. NATURAL KILLER (NK) CELLS • Lymphocytes that destroy virus-infected and tumor cells. • Not specific. • Do not require antigen stimulation. • Not MHC restricted. • Not phagocytic, but must contact cell in order to lyse it. 21
- 22. • They are stimulated phagocytes. • Stimulated by ingestion of antigen or by cytokines. • Larger and more effective phagocytes. • Enhanced ability to eliminate intracellular bacteria, virus-infected and cancerous cells. ACTIVATED MACROPHAGES 22
- 23. T-CELLS AND CELL-MEDIATED IMMUNITY • Recognize foreign antigens on the surface of cells, organisms, or tissues. • Regulate proliferation and activity of other cells of the immune system. • Provide defense against: • Bacteria and viruses that are inside host cells and are inaccessible to antibodies. • Fungi, protozoa, and helminths • Cancer cells • Involved in harmful effects of hypersensitivity reaction type 4, graft or transplant rejections, skin tests, and granuloma formation. 23
- 24. HYPERSENSITIVITY • Hypersensitivity reactions are: • Injurious, or pathologic immune reactions. • A reflection of excessive or aberrant immune responses. • They may occur in two situations: • Foreign antigens may cause tissue injury. • Immune responses may be directed against self (autologous) antigens, due to failure of self-tolerance. 24
- 27. AETIOLOGY OF TYPE IV HYPERSENSITIVITY Major causes of T cell–mediated hypersensitivity reactions include: 1. Autoimmunity • Usually directed against cellular antigens with restricted tissue distribution. • Tend to be limited to a few organs and usually are not systemic. 2. Exaggerated or persistent responses to environmental antigens • e.g. T cell–mediated immune response develops against protein antigens of Mycobacterium tuberculosis. o Response becomes chronic because the infection is difficult to eradicate. o Resultant granulomatous inflammation causes injury to normal tissues at the site of infection. 27
- 28. T-CELLS AND CYTOKINES • Cytokines produced by TH1 cells inhibit TH2 cells; and, vice versa. • An immune response is often dominated by a cell-mediated response or an antibody response. • Some pathogens have evolved strategies to shift the immune response toward the less effective type for that pathogen. TH0 TH2 TH1 IL-2 IL-4 IFN- IL-2 IFN- IL-4 IL-5 IL-10 28
- 29. CELL-MEDIATED IMMUNITY AND SUPERANTIGENS Toxins are called superantigens stimulate large numbers of T cells. bind to invariant parts of T cell receptors on many different clones of T cells regardless of antigen specificity. Production of large amounts of inflammatory cytokines, causing a syndrome similar to septic shock. Excessive polyclonal T cell activation by certain microbial toxins produced by some bacteria and viruses 29
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- 31. MECHANISMS OF T-CELL-MEDIATED INJURY Abbas, A. K., Lichtman, A. H., & Pillai, S. (2016). Basic Immunology: Functions and Disorders of the Immune System. 31
- 32. CLASSIFICATION OF AUTOIMMUNE DISEASES Organ-Specific Systemic Diseases Mediated by Antibodies Autoimmune hemolytic anemia Systemic lupus erythematosus Autoimmune thrombocytopenia Autoimmune atrophic gastritis of pernicious anemia Myasthenia gravis Graves disease Goodpasture syndrome Diseases Mediated by T Cells Type 1 diabetes mellitus Rheumatoid arthritis Multiple sclerosis Systemic sclerosis (scleroderma) Sjögren’s syndrome Diseases Postulated to be Autoimmune Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis Primary biliary cirrhosis Polyarteritis nodosa Autoimmune (chronic active) hepatitis Inflammatory myopathies 32
- 33. TYPE 1 DIABETES MELLITUS & T-CELLS • Ultimately, auto-aggressive T-cells invade pancreatic islets focusing destructive force on the beta cells that produce insulin. • The initial insult may be solely inflammation but nonetheless results in loss of insulin production. • Insulitis is only present in islets with beta cells, which implies that the islet infiltration is a beta-cell driven process. • Immunosuppressive drugs (e.g. Cyclosporin A) have been shown to delay the disease progress. Insulitis. Inflammation of the pancreatic islets with mononuclear cells including T-cells is the hallmark of Type 1 diabetes (courtesy A. van Halteren) 33
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- 35. RHEUMATOID ARTHRITIS & T-CELLS • T-cells infiltrate into the synovial membrane where they initiate and maintain activation of macrophages and synovial fibroblasts, transforming them into tissue-destructive effector cells. Later, formation of pannus. • Abatacept [Orencia®] (soluble cytotoxic- T-lymphocyte-associated protein 4– immunoglobulin), which binds with high affinity to CD80/CD86 and effectively suppresses inflammatory activity in RA. 35
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- 37. MULTIPLE SCLEROSIS & T-CELLS • MS is a cell-mediated autoimmune disease directed against CNS myelin antigens that involves both CD4+ and CD8+ cells leading to myelin sheath destruction. • Peripherally activated T cells cross the blood-brain barrier into the central nervous system, where they are re-activated and secrete cytokines to exert their effector functions. 37
- 38. SYSTEMIC SCLEROSIS & T-CELLS • T cells show signs of antigen-induced activation; T cells of TH2 type are increased and produce pro- fibrotic cytokines interleukin (IL)-4, IL-13, and IL- 31. • CD4+ cytotoxic T lymphocytes are increased in skin lesions, and cause fibrosis and endothelial cell apoptosis. • Circulating T follicular helper (TFH) cells are increased in SSc, produce IL-21 and promote plasmablast antibody production. • On the other hand, regulatory T cells are impaired. 38
- 40. T-CELLS AND TRANSPLANT (GRAFT) REJECTION • Transplantation is the most effective treatment for end-stage organ failure. • Organ survival is limited by immune rejection and the side effects of immunosuppressive regimens. • T cells are central to the process of transplant rejection through: • Allorecognition of foreign antigens leading to their activation. • Orchestration of an effector response that results in organ damage. 40
- 41. IMMUNE RESPONSE AGAINST TRANSPLANTS 41
- 44. REFERENCES • Abbas, A. K., Lichtman, A. H., & Pillai, S. (2016). Basic Immunology: Functions and Disorders of the Immune System. • Beacher, C. et. al., (2018). Multiple Sclerosis: Mechanisms and Immunotherapy. Neuron Review. Cell Press. https://doi.org/10.1016/j.neuron.2018.01.021 • Cabrera, M., Rigby, S., Raghavendra, M. (2012). Targeting Regulatory T Cells In The Treatment Of Type 1 Diabetes Mellitus. Current molecular medicine. 12. 10.2174/156652412803833634 • Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Chapter 8, T Cell-Mediated Immunity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10762/ (Accessed: December 18, 2022) • Kaiser, G. (2022) 14.1: Cell-mediated immunity - an overview, Biology LibreTexts. Libretexts. Available at: https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Kaiser)/Unit_6%3A_Adaptive_Immunity/14%3A_Cell- Mediated_Immunity/14.1%3A_Cell-Mediated_Immunity_-_An_Overview (Accessed: January 10, 2023). • Maehara, T. et al. (2020) Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis, The Journal of Clinical Investigation. American Society for Clinical Investigation. Available at: https://www.jci.org/articles/view/131700 (Accessed: January 5, 2023). • Sakkas LI, Bogdanos DP. The Role of T Cells in Systemic Sclerosis: An Update. Immuno. 2022; 2(3):534-547. https://doi.org/10.3390/immuno2030034 (Accessed: January 8, 2023) • Tarke, A., et al., Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID- 19 cases. Cell Rep Med 2, 100204 (2021). • Wagner, D. (2011). The Role of T Cells in Type 1 Diabetes. Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy. doi: 10.5772/22040 44
- 45. Thank you for listening!
Editor's Notes
- (e.g., skin, mucous membranes, sebaceous secretions, pinocytosis, or phagocytosis).
- Most T cells recognize only protein antigens, whereas B cells and antibodies are able to recognize many different types of molecules, including proteins, carbohydrates, nucleic acids, and lipids
- Activating antigen-specific cytotoxic T-lymphocytes (CTLs) that are able to destroy body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens; Activating macrophages and NK cells, enabling them to destroy intracellular pathogens; and, 3. Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive and innate immune responses. - Cytokines are chemical messengers of immune cells
- T Lymphocytes are the main coordinators and effectors of cell-mediated immunity Non-specific components: NK Cells and Activated Macrophages
- Hence “T” cells Thymic cortical cells express MHC class 1 and MHC class 2 antigens In positive selection: it tests if T-cell receptors can bind to MHC appropriately (not too strongly or too weakly). In negative selection: it tests if T-cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells Dysfunctional T-cells or those that do not bind to antigen, undergo apoptosis.
- Binding of a TCR to its specific antigen initiated T cell activation. The cells of the acquired immune system (B cells, T cells) are activated upon antigen recognition.
- Monovalent, i.e. has one binding site. Bivalent, i.e. has two binding sites.
- In addition, T-cells bind with their cluster of differentiation (CD) CD4 binds to MHC 2 CD8 binds to MHC 1
- T Cells are largely divided into Cytotoxic T-Cells (CD8+), T-Helper cells (CD4+) and Regulatory T Cells Other subtypes include memory T cells, suppressor T cells and Natural killer T Cells
- (e.g.: macrophage, dendritic cells, and B cells).
- Non-specific cellular component involved in cell-mediated immunity: NK Cells
- Nonspecific cellular components: Activated Macrophages
- Regulate; such as B- Cells, macrophages and neutrophils i.e. intracellular pathogens
- Cytokines are the chemical messengers of immune cells; and, they stimulate and/or regulate immune responses. Interleukins: communication between WBCs Interferons: protect against viral infections Chemokines: Attract WBC to affected areas
- T-cell dependent immune-mediated disease in which the insulin-producing pancreatic beta cells are destroyed.
- Cytolytic molecules: Fas ligand (fasL), perforin (PFN), granzyme (GZN)
- Pannus: late, inactive and irreversible manifestation of RA.
- Peripherally activated T cells cross the blood-brain barrier (BBB) into the central nervous system (CNS), where they are re-activated and secrete cytokines to exert their effector functions. T helper (Th)-1 cells produce their lineage-defining cytokine, IFNg, as well as TNFa, while Th17 cells secrete their defining cytokine IL-17, as well as IL-21 and IL-22, and can also express IFNg, which contributes to their pathogenicity. CD8+ effector T cells (Teffs) can also be a source of IL-17 and IFNg. This cytokine secretion leads to the activation of CNS-resident immune cells (such as microglia, astrocytes, and macrophages), as well as to the production of cytokines, increased antigen-presenting cell (APC) function, and the enhanced production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). CD8 T cells can also release cytolytic granules causing axonal dissection. Effector T cells can be regulated in the periphery or in the CNS by FoxP3+ regulatory T cells (Tregs) and by Tr1 cells, CD8 Tregs, natural killer cells (NK cells), and regulatory B (Breg) cells.
- SSc is a chronic disease characterized by microvasculopathy, autoantibodies, and fibrosis.
- Graft antigens that are expressed on donor dendritic cells or captured by recipient dendritic cells are transported to peripheral lymphoid organs where alloantigen-specific T cells are activated (the sensitization step). The T cells migrate back into the graft and destroy graft cells (rejection). Antibodies are also produced against graft antigens and can contribute to rejection (not shown). The example shown is that of a kidney graft, but the same general principles apply to all organ grafts.
- A representative histologic appearance of each type of rejection is shown on the right. A, In hyperacute rejection, preformed antibodies react with alloantigens on the vascular endothelium of the graft, activate complement, and trigger rapid intravascular thrombosis and necrosis of the vessel wall. B, In acute rejection, CD8+ T lymphocytes reactive with alloantigens on graft endothelial cells and parenchymal cells or antibodies reactive with endothelial cells cause damage to these cell types. Inflammation of the endothelium is called endothelialitis. The histology shows acute cellular rejection in i and humoral (antibody-mediated) rejection in ii. C, In chronic rejection with graft arteriosclerosis, T cells reactive with graft alloantigens may produce cytokines that induce inflammation and proliferation of intimal smooth muscle cells, leading to luminal occlusion.