BMF_T cells_2023xy PW.pptx

19th November 2023 Adaptive Immunity - T cells Dr Patrick Walsh Class Year 1 Module BMF Title Adaptive Immunity – T cells LECTURE LEARNING OUTCOMES By the end of this lecture you should be able to: RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H • Outline the key roles of T-cells •...

19th November 2023 Adaptive Immunity - T cells Dr Patrick Walsh Class Year 1 Module BMF Title Adaptive Immunity – T cells LECTURE LEARNING OUTCOMES By the end of this lecture you should be able to: RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H • Outline the key roles of T-cells • Describe the stages of T cell development including T cell receptor rearrangement • Describe the process of negative and positive selection for T cells • Describe T cell activation • Define the key effector functions of T helper cells and cytotoxic T cells • Identify the different T helper cell subsets (Th1, Th2, Th17, Treg) and understand their different roles in infection • Outline central and peripheral tolerance for T cells • List diseases associated with T cell deficiencies Dr Chiara De Santi, Adaptive Immunity T cells RECAP – Antigen presentation T H E W O R L D T O B E T T E R H E A LT H • MHC class II and MHC class I are cell surface receptors specialised in presenting antigens • Present only peptide antigens T helper cell • TCR recognises presented peptides, binds and becomes activated TCR MHC class I RCSI LEADING Antigen • Communicating about the pathogen to the adaptive immune arm T Epithelium Endothelium Fibroblasts (all nucleated cells) Dr Chiara De Santi, Adaptive Cytotoxic T Cell Immunity • MHC-peptide complexes are recognised by T cells T cells MHC class II – T helper cell MHC class I – Cytotoxic T cell Dendritic cells (DCs) travel through lymphatic vessels to transport antigens and present them to T cells in the paracortical region of the lymph nodes. RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H KEY ROLES OF T-CELLS • T cells are cells of the adaptive immune system (antigen-specific response) • They have two main functions:  Helper T cells (Th)  they ‘help’ the immune responses  Cytotoxic T cells (CTL)  they kill cells infected by intracellular pathogens (and cancerous cells!) Dr Chiara De Santi, Adaptive Immunity T cells Unique features of T cells • T cells must interact with other cells T H E W O R L D T O B E T T E R H E A LT H • TCR recognises antigen bound to MHC T helper cell • Each T cell has a unique TCR - hugely diverse repertoire • Once a T cell is activated – clonal expansion TCR MHC class I • T helper and cytotoxic T cells have different effector functions Antigen RCSI LEADING T Epithelium Endothelium Fibroblasts (all cells) Dr Chiara De Santi, Adaptive Cytotoxic T Cell Immunity T cells • Generate memory T cells that live for >20 years Pertinent Questions T H E W O R L D T O B E T T E R H E A LT H • Where do the T cells come from? • How do they express TCR with specific affinity for peptide? • What is the activation process and why is it important? RCSI LEADING • What is the difference between T helper and cytotoxic T cells? Dr Chiara De Santi, Adaptive Immunity T cells LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function T H E W O R L D T O B E T T E R H E A LT H Lymph Nodes Thymus (primary lymphoid tissue)(secondary lymphoid tissue) Direct KILLING CD8+ T cells (Cytotoxic) CD4+ T cells (Helper) Immature T cells • T cell is ACTIVATED • Clonal expansion of antigen specific clone • Differentiation into Effector cell RCSI LEADING • TCR rearrangement • Selection process • Differentiation into CD4/CD8 lineage • Now known as Naïve T cells Dr Chiara De Santi, Peripheral Tissue (any tissue) Adaptive Immunity T cells HELP given to B cells and macrophag es Antibody productio n LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function T H E W O R L D T O B E T T E R H E A LT H Lymph Nodes Thymus (primary lymphoid tissue)(secondary lymphoid tissue) Peripheral Tissue (any tissue) Direct KILLING CD8+ T cells (Cytotoxic) CD4+ T cells (Helper) Immature T cells INITIAL ANTIGEN EXPOSURE RCSI LEADING PRIOR TO ANTIGEN EXPOSURE HELP given to B cells and macrophag es Antibody productio n RESPONSE TO RECOGNISED ANTIGEN Dr Chiara De Santi, Adaptive Immunity T cells T H E W O R L D T O B E T T E R H E A LT H RCSI LEADING T CELL DEVELOPMENT Dr Chiara De Santi, Adaptive Immunity T cells • Immature T cells migrate from bone marrow to thymus • Undergo development in thymus • Mature cells exit to the circulation as NAÏVE T cells as either CD4+ or CD8+ RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H T cell development – takes place in the thymus Dr Chiara De Santi, Adaptive Immunity T cells T cell development – CHECKPOINTS Checkpoints are required to ensure the selection of appropriate T cells T H E W O R L D T O B E T T E R H E A LT H 1. Do you have a TCR? 2. Can you recognise self-MHC (positive selection)? 3. Do you recognise selfantigen (negative selection)? RCSI LEADING In fact, 98% of all Thymocytes (immature T cells) will not leave Thymus – majority die Why??? Dr Chiara De Santi, Adaptive Immunity T cells T cell receptor (TCR) • Millions of T cells with a single TCR • It is a membrane bound protein composed of an a chain and b chain • Each chain contains one variable region (V) and one constant (C) region • V region is the antigen binding site which is different for every T cell clone • Constant region doesn’t change T H E W O R L D T O B E T T E R H E A LT H Variable region RCSI LEADING Constant region Dr Chiara De Santi, Adaptive Immunity T cells T cell development – CHECKPOINTS Checkpoints are required to ensure the selection of appropriate T cells 1. Do you have a TCR? Yes! T H E W O R L D T O B E T T E R H E A LT H - Cells at this point are also CD4 and CD8 positive - CD4 and CD8 are co-receptors Double Positive CD4+ CD8+ 2. Can you recognise self-MHC (positive selection)? RCSI LEADING 3. Do you recognise selfantigen (negative selection)? Dr Chiara De Santi, Adaptive Immunity T cells CD – Cluster of Differentiation POSITIVE SELECTION • The TCR interacts with MHC expressed on epithelial cells and dendritic cells in the thymus T H E W O R L D T O B E T T E R H E A LT H • Immature T cells bind MHC and get a positive signal to survive Dendritic cell RCSI LEADING • Depending on whether the interaction occurred with MHC class I or MHC class II results in a single positive CD8 or CD4 T cell Positive selection – Dr Chiara De retains T cells that recognise MHC - enables recognition of Santi, Adaptive Immunity T cells self! • MHC in the thymus only expresses SELF-PEPTIDE! • Occurs early in development (7-8 weeks gestation) • Does the TCR bind tightly to selfpeptide?  T cell dies • Does the TCR bind self-peptide weakly/moderately/ not at all? T cell lives (= NEGATIVE SELECTION) RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H NEGATIVE SELECTION Protects against autoimmunity Dr Chiara De Santi, Adaptive Immunity T cells CENTRAL T cell development – CHECKPOINTS Checkpoints are required to ensure the selection of appropriate T cells 1. Do you have a TCR? Yes! Double Positive CD4+ CD8+ T H E W O R L D T O B E T T E R H E A LT H - Cells at this point are CD4 and CD8 positive - CD4 and CD8 are co-receptors Single Positive CD4+ or CD8+ 2. Can you recognise self-MHC (positive selection)? Yes! - Cells at this point are CD4 or CD8 single positive Naïve CD4+ or CD8+ RCSI LEADING 3. Do you recognise selfantigen (negative selection)? Naïve T cells circulate in lymph nodes Only weakly! to await antigen Dr Chiara De Santi, Adaptive Immunity T cells FILL THE BOXES! TCR MHC class I Antigen CD8 coreceptor T H E W O R L D T O B E T T E R H E A LT H T helper cell Dendritic cells Macrophages B cells T All nucleated cells Cytotoxic T cell CD4 coreceptor RCSI LEADING APC stands for: A. Activated Patrolling Cell B. Antigen Presenting Cell Dr Chiara De C. S a nAnti t i , A d Pus a p t i v eComplex Immunity T cells TCR stands for: A. Tandem Complex Reaction B. Tea Cup Rearrangement C. T Cell Receptor T H E W O R L D T O B E T T E R H E A LT H RCSI LEADING T CELL ACTIVATION Dr Chiara De Santi, Adaptive Immunity T cells T CELL ACTIVATION OCCURS IN LYMPH NODES T H E W O R L D T O B E T T E R H E A LT H • Naive T cell - Never met antigen • Circulates in secondary lymph organs • Diverse array of T cells each with a single TCR • Once TCR recognises an antigen bound to MHC on DC RCSI LEADING T cell is activated Dr • This specific T cell clone proliferates (clonal expansion) • Naïve T cell differentiates into an effector T cell • It leaves the lymph node to carry out its effector functions Chiara De Santi, Adaptive Immunity T cells T H E W O R L D T O B E T T E R H E A LT H Activation of Naïve T cells requires 3 signals CD B 28 RCSI LEADING 7 ature reviews Immunology 14, Taku Kambayashi & Terri M. Laufer, p719-730 Dr Chiara De Santi, Adaptive Immunity T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H SIGNAL 1 – antigen specific Dr Chiara • Antigen is the necessary first signal for activation of T cells • The TCR recognises a peptide presented on MHC II molecule • CD4 co-receptor interacts with residues on the side of MHC class II • Adhesion molecules on T cells such as integrin also bind to ligands on APC to stabilise the synapse + • T cell CD4 T cell shown – samesignal for CD8+2T to cellbecome fully is primed but here requires recognising MHC class I activated De Santi, Adaptive Immunity T cells SIGNAL 2 – co-stimulation RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H DC Dr Chiara CD4+ T cell • The proliferation and differentiation of naïve T cells require co-stimulation • Microbes will stimulate APCs to express costimulatory receptors such as B7 (this only occurs in presence of microbes) • Binds to the T cell surface receptor CD28 • Once CD28 is engaged then T cells are properly activated to promote the survival, proliferation and differentiation of De Santi, Adaptive Immunity T cells T H E W O R L D T O B E T T E R H E A LT H SIGNAL 3 – instructive cytokines DC CD4+ T cell RCSI LEADING • Activated APC produces instructive cytokines that aid the differentiation of certain CD4+ T cell subsets Dr Chiara De Santi, – IL-12 and IFNγ stimulate Th1 subset – IL-10 stimulates Th2 Adaptive Immunity T cells – IL-23 stimulates Th17 Cytokines direct different CD4+ T cell subsets T H E W O R L D T O B E T T E R H E A LT H Th1 Helminth Intracellular Bacterial Infections IL-12 IL-10 Th2 Helminth Infections IL-23 RCSI LEADING Th17 Dr Chiara De Santi, Adaptive Immunity T cells Extracellular bacterial/yeast infections RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H CLONAL EXPANSION Dr • Activated T cells will rapidly start to produce IL-2, a T cell growth factor • Antigen-specific activated T cells are cloned into large populations (autocrine signalling via IL-2), i.e. one activated T cell now must clone itself to make lots of T cells recognising the same antigen • A fraction of T cells develop into memory T cells which circulate for years ready to respond to the same microbe Chiara De Santi, Adaptive Immunity T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H EFFECTOR T CELL ENTERS SYSTEMIC CIRCULATION Dr Chiara De Santi, Adaptive Immunity T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H T CELL EFFECTOR FUNCTION (OCCURS IN THE PERIPHERY) Dr Chiara De Santi, Adaptive Immunity T cells T CELLS/LYMPHOCYTES • Two different types of T cell with distinct functions: 1.T helper cells (CD4+): ‘helps’ to mount the appropriate immune response - Th1 subset - Th2 subset - Th17 subset - T regulatory subset RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H • T cells need to interact with another cell to carry out their effector function 2. Cytotoxic T cell (CD8+): -kill infected or altered cell – killer T cell Dr Chiara De Santi, Adaptive Immunity T cells Resting T lymphocyte Activated T lymphocyte T helper subsets RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H Activating cytokines (produced by APC) T helper subset Effector cytokines (produced by T cell) Th1 IFN-γ Th2 IL-4 IL-5 IL-13 Th17 IL-17 IL-22 IL-12 IL-10 IL-23 Target cells and immune context Macrophages & Cytotoxic T cells (intracellular pathogens) Eosinophils (helminth infections) & Mast cells (Allergy) + B cells to produce antibodies Neutrophils (extracellular bacterial/yeast infections) + Treg (regulatory T cells) – the production of IL-10 helps Treg switch off Th1, Th2 & Th17 responses Dr Chiara De Santi, Adaptive Immunity T cells Cytotoxic T Lymphocyte (CTL) – CD8+ T cell T H E W O R L D T O B E T T E R H E A LT H • Virally infected cell will display viral antigens on MHC class I molecule • Activated cytotoxic T cells bind antigen on MHC class I • Packed full of vesicles with toxic enzymes for killing • Released once CTL is activated – Perforin forms pores in membrane RCSI LEADING – Granzymes activate apoptosis • They don’t kill pathogens, they kill cells infected by pathogens!!! Dr Chiara De Santi, Adaptive Immunity T cells CTL T H E W O R L D T O B E T T E R H E A LT H Fatima, a 30-year-old accountant, picks up a helminthic infection while swimming in a parasite-infested river in West Africa. Following interaction with the patient's innate immune system, what subtype of CD4+ T cells is expected in response to this type of infection? A. Th1 B. Th2 C. Treg D. Th17 RCSI LEADING Which of the following cytokines do Th2 secrete? A. IL-5 B. INF-γ C. IL-17 Which cells are mostly activated by Th2? A. macrophages B. neutrophils C. eosinophils Dr Chiara De Santi, Adaptive Immunity T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H DISORDERS ASSOCIATED WITH T CELL DYSFUNCTION Dr Chiara De Santi, Adaptive Immunity T cells RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H CENTRAL AND PERIPHERAL TOLERANCE Dr Some key definitions…. • Self-tolerance  unresponsiveness of T cells to self antigens. This is important because it prevents autoimmunity. It is achieved through:  Central Tolerance  tolerance induced early development of T cells in the thymus (‘central’ or primary lymphoid organ)  it comprises mechanisms that eliminate most of autoreactive T cells (negative selection)  Peripheral Tolerance  tolerance induced when T cells migrate to the lymph nodes (‘peripheral’ or secondary lymphoid organs)  it eliminates T cells which recognise self-antigens not expressed in the thymus • When tolerance fails  auto-reactive T cells recognise selfantigens  autoimmunity  autoimmune disorders (such as Chiara De Santi, Adaptive Immunity T cells T cell Immunodeficiencies RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H DiGeorge syndrome – a deletion on chromosome 22 • A small deletion on Chromosome 22  thymus is small or absent  poor T cell production • Individuals susceptible to recurrent infections with intracellular pathogens • Also associated with problems across multiple organs, e.g. congenital heart problems, abnormal facial features, learning difficulties, psychiatric issues, hypocalcaemia… Severe Combined Immunodeficiency (SCID) • Umbrella of rare disorders caused by mutations in different genes that impact on T and B cells  low/absent T/B cells • Typically fatal in first 2 years of life, with severe bacterial, viral and fungal infections • Examples: X-linked severe SCID (most common worldwide) or Adenosine deaminase deficiency (most common in Ireland) Dr Chiara De Santi, Adaptive Immunity T cells SUMMARY T cell Maturation T cell Activation T cell Effector Function T H E W O R L D T O B E T T E R H E A LT H Lymph Nodes Thymus (primary lymphoid tissue)(secondary lymphoid tissue) Direct KILLING CD8+ T cells (Cytotoxic) CD4+ T cells (Helper) Immature T cells • T cell is ACTIVATED • Clonal expansion of antigen specific clone • Differentiation into Effector cell RCSI LEADING • TCR rearrangement • Selection process • Differentiation into CD4/CD8 lineage • Now known as Naïve T cells Dr Chiara De Santi, Peripheral Tissue (any tissue) Adaptive Immunity T cells HELP given to B cells and macrophag es Antibody productio n Tu e s d a y , 1 1 t h O c t 2 0 2 2 Thank you Dr Patrick Walsh Class Year 1 Module Foundations for Practice 1 Click to edit master title style Title Adaptive Immunity – T cells