Adaptive Immunity - T Cells PDF 2024 (RCSI)

November 2024 Adaptive Immunity - T cells Dr Patrick Walsh Class Year 1 ModuleBMF Title Adaptive Immunity – T cells  IMMUNOLOGY LECTURES OUTLINE...

November 2024 Adaptive Immunity - T cells Dr Patrick Walsh Class Year 1 ModuleBMF Title Adaptive Immunity – T cells  IMMUNOLOGY LECTURES OUTLINE TIME Barrier Immunity Physical barrier (Intro to Instant Imm lecture)Infection Mechanical barrier (Intro to Imm lecture) T H E W O R L D T O B E T T E R H E A LT H Chemical barrier (Intro to Imm lecture) Minutes- Hours Innate Immunity Cytokines (Intro to Imm lecture) Inflammation (Inn Imm lecture) Days-weeks Complement (Inn Imm lecture) Antigen Presentation (Inn Imm RCSI LEADING lecture) Response to Extracellular Inf Adaptive Immunity lecture T cells – Cytotoxic and Dr Chiara Help (T cell lecture) Response De Santi, Introduction to the imm unology to Intracellular Inf  LECTURE LEARNING OUTCOMES By the end of this lecture you should be able to: Outline the key roles of T-cells Describe the stages of T cell development including T cell T H E W O R L D T O B E T T E R H E A LT H 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 RCSI LEADING Outline central and peripheral tolerance for T cells List diseases associated with T cell deficiencies Dr Chiara De Santi, Adaptive Immunity T cells  KEY ROLES OF T-CELLS T H E W O R L D T O B E T T E R H E A LT H T cells are cells of the adaptive immune system (antigen-specific response) They have two main functions: RCSI LEADING  Helper T cells (Th)  they ‘help’ the immune responses  Cytotoxic T cells (CTL)  they kill cells infected by intracellular Dr pathogens (and cancerous cells!) Chiara De Santi, Adaptive Immunity T cells  RECAP – Antigen presentation MHC class II and MHC class I are cell surface receptors specialised in presenting antigens Present only peptide antigens T H E W O R L D T O B E T T E R H E A LT H MHC-peptide complexes are recognised T helper cell by T cells MHC class I TCR TCR recognises presented peptides, Antigen binds and becomes activated Communicating about the pathogen to the adaptive immune arm RCSI LEADING T Epithelium Endothelium Cytotoxic T Cell MHC class II – T helper cell Fibroblasts (all nucleated cells) MHC class I – Cytotoxic T cell Dr Chiara De Santi, Adaptive Immunity T cells  Unique features of T cells T cells must interact with other cells TCR recognises antigen bound to MHC T H E W O R L D T O B E T T E R H E A LT H Each T cell has a unique TCR - hugely T helper cell diverse repertoire Once a T cell is activated – clonal expansion TCR MHC class I Antigen T helper and cytotoxic T cells have different effector functions T Generate memory T cells that live for >20 RCSI LEADING Epithelium Endothelium Cytotoxic T Cell years Fibroblasts (all cells) Dr Chiara De Santi, Adaptive Immunity T cells  Pertinent Questions Where do the T cells come from? How do they express TCR with specific affinity for T H E W O R L D T O B E T T E R H E A LT H peptide? What is the activation process and why is it important? What is the difference between T helper and RCSI LEADING 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 Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H KILLING CD8+ T cells (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and TCR rearrangement T cell is ACTIVATED macrophag Selection process Clonal expansion of es Differentiation into antigen specific Antibody CD4/CD8 lineage clone productio RCSI LEADING n Now known as Naïve T Differentiation into cells Effector cell Dr Chiara De Santi, Adaptive Immunity T cells  LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H CD8+ T cells KILLING (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and macrophag PRIOR TO INITIAL es ANTIGEN EXPOSURE ANTIGEN EXPOSURE Antibody productio RCSI LEADING 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 T CELL DEVELOPMENT RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  thymus Immature T cells T H E W O R L D T O B E T T E R H E A LT H 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 Naïve = they haven’t met any antigen Dr yet 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? T H E W O R L D T O B E T T E R H E A LT H 2. Can you recognise an MHC (positive selection)? 3. Do you recognise self- antigen (negative selection)? In fact, 98% of all Thymocytes (immature T RCSI LEADING 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 Variable It is a membrane bound T H E W O R L D T O B E T T E R H E A LT H region protein composed of an a chain and b chain Each chain contains one Constant variable region (V) and one region constant (C) region V region is the antigen binding site which is different for every T cell clone RCSI LEADING Constant region doesn’t change Dr Chiara De Santi, Adaptive Immunity T cells How do we create T cells able to respond to all possible antigens? At any one time we have millions of T cells in our body, each having a TCR with a different specificity for antigen How? During T cell development gene rearrangement of TCR genes (VDJ recombination) occurs and variable TCRs T H E W O R L D T O B E T T E R H E A LT H with unique specificities are generated! VDJ recombination – randomly combine V(D)J genes to form VDJ or VJ segments  1014 different combinations!!!!! α- β-chain Rearranged at chain the DNA level – once changed can’t alter – T RCSI LEADING cell has a single receptor Dr Chiara De Santi, Adaptive Immunity T cells throughout life  T cell development – CHECKPOINTS Checkpoints are required to ensure the selection of appropriate T cells 1. Do you have a TCR? Yes! Double - Cells at this point are also CD4 Positive and CD8 positive T H E W O R L D T O B E T T E R H E A LT H CD4+ CD8+ - CD4 and CD8 are co-receptors 2. Can you recognise an MHC (positive selection)? 3. Do you recognise self- antigen (negative selection)? CD – Cluster of Differentiation RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  The TCR interacts with MHC POSITIVE SELECTION expressed on epithelial cells and dendritic cells in the thymus Immature T cells bind MHC and T H E W O R L D T O B E T T E R H E A LT H get a positive signal to survive Dendritic cell Depending on whether the interaction occurred with MHC class I or MHC class II results in a single positive CD8 or CD4 T cell RCSI LEADING Positive selection – retains T cells that recognise MHC 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! Double - Cells at this point are also CD4 Positive and CD8 positive T H E W O R L D T O B E T T E R H E A LT H CD4+ CD8+ - CD4 and CD8 are co-receptors 2. Can you recognise an MHC (positive selection)? Yes! - Cells at this point are CD4 or CD8 single positive 3. Do you recognise self- CD – Cluster of Differentiation RCSI LEADING antigen (negative selection)? Dr Chiara De Santi, Adaptive Immunity T cells  NEGATIVE SELECTION MHC in the thymus only expresses SELF-PEPTIDE! Occurs early in development (7-8 weeks gestation) T H E W O R L D T O B E T T E R H E A LT H Does the TCR bind tightly to self- peptide?  T cell dies Does the TCR bind self-peptide weakly/moderately/not at all? T cell lives (= NEGATIVE SELECTION) RCSI LEADING 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 - Cells at this point are CD4 and CD8 Positive positive T H E W O R L D T O B E T T E R H E A LT H CD4+ CD8+ - CD4 and CD8 are co-receptors Single 2. Can you recognise an MHC Positive CD4+ or (positive selection)? Yes! CD8+ - Cells at this point are CD4 or CD8 Naïve CD4+ or single positive CD8+ 3. Do you recognise self- RCSI LEADING antigen (negative selection)? Naïve T cells circulate in lymph nodes Only weakly! to await antigen Dr Chiara De Santi, Adaptive Immunity T cells  LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H CD8+ T cells KILLING (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and macrophag PRIOR TO INITIAL es and ANTIGEN EXPOSURE ANTIGEN EXPOSURE Antibody other productio immune RCSI LEADING n cells RESPONSE TO RECOGNISED ANTIGEN Dr Chiara De Santi, T cell Biology  FILL THE BOXES! TCR MHC class I Antigen CD8 co- T helper cell receptor T H E W O R L D T O B E T T E R H E A LT H Dendritic cells Macrophages T B cells All nucleated cells Cytotoxic T cell CD4 co- receptor APC stands for: TCR stands for: A. Activated Patrolling A. Tandem Complex Reaction RCSI LEADING Cell B. Tea Cup Rearrangement B. Antigen Presenting C. T Cell Receptor Cell Dr Chiara D e C. S a nAnti t i , A d Pus a p t i v eComplex Immunity T cells T H E W O R L D T O B E T T E R H E A LT H T CELL ACTIVATION RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  T CELL ACTIVATION OCCURS IN LYMPH NODES 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 T H E W O R L D T O B E T T E R H E A LT H to MHC on DC T cell is activated This specific T cell clone proliferates (clonal expansion) Naïve T cell differentiates into an RCSI LEADING effector T cell It leaves the lymph node to carry out Dr its effector functions Chiara De Santi, Adaptive Immunity T cells Lymph Node  Activation of Naïve T cells requires 3 signals T H E W O R L D T O B E T T E R H E A LT H B7 CD2 8 RCSI LEADING ature reviews Immunology 14, Taku Kambayashi & Terri M. Laufer, p719-730 Dr Chiara De Santi, Adaptive Immunity T cells  SIGNAL 1 – antigen specific T H E W O R L D T O B E T T E R H E A LT H 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 RCSI LEADING to ligands on APC to stabilise the synapse T cell CD4 is primed + but here T cell shown requires – samesignal for CD8+2T to cellbecome fully recognising MHC class I Dr Chiara De activated Santi, Adaptive Immunity T cells  SIGNAL 2 – co-stimulation DC CD4+ T cell T H E W O R L D T O B E T T E R H E A LT H 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 RCSI LEADING microbes) Binds to the T cell surface receptor CD28 Dr Chiara Once CD28 is engaged then T cells are properly activated to De Santi, Adaptive Immunity T cells  SIGNAL 3 – instructive cytokines T H E W O R L D T O B E T T E R H E A LT H DC CD4+ T cell Activated APC produces instructive cytokines that aid the differentiation of certain CD4+ T RCSI LEADING cell subsets – IL-12 and IFNγ stimulate Th1 subset – IL-4 stimulates Th2 (although this is a product of Th2 cells, so Dr Chiara De Santi, Adaptive Immunity T cells  Cytokines direct different CD4+ T cell subsets Th1 Intracellular Bacterial Infections T H E W O R L D T O B E T T E R H E A LT H Helminth IL-12 Th2 Helminth Infections IL-4? IL-23 Extracellular Th17 bacterial/yeast RCSI LEADING infections Dr Chiara De Santi, Adaptive Immunity T cells  CLONAL EXPANSION T H E W O R L D T O B E T T E R H E A LT H 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 RCSI LEADING cells recognising the same antigen A fraction of T cells develop into memory T cells which Dr circulate for years ready to respond to the same microbe Chiara De Santi, Adaptive Immunity T cells  LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H CD8+ T cells KILLING (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and macrophag PRIOR TO INITIAL es and ANTIGEN EXPOSURE ANTIGEN EXPOSURE Antibody other productio immune RCSI LEADING n cells RESPONSE TO RECOGNISED ANTIGEN Dr Chiara De Santi, T cell Biology  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 (OCCURS IN THE PERIPHERY) RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  EFFECTOR T CELL ENTERS SYSTEMIC CIRCULATION T H E W O R L D T O B E T T E R H E A LT H RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  T CELLS/LYMPHOCYTES T cells need to interact with another cell to carry out their effector function Two different types of T cell with T H E W O R L D T O B E T T E R H E A LT H distinct functions: 1.T helper cells (CD4+): ‘helps’ to mount the appropriate immune response Resting Activated - Th1 subset T lymphocyte T lymphocyte - Th2 subset - Th17 subset - T regulatory subset RCSI LEADING 2. Cytotoxic T cell (CD8+): -kill infected or altered cell – killer T Dr Chiara De Santi, Adaptive Immunity T cells  T helper subsets Activating T helper subset Effector Target cells and cytokines cytokines immune context (produced by (produced by T APC) cell) Th1 IFN-γ Macrophages & Cytotoxic T cells (intracellular T H E W O R L D T O B E T T E R H E A LT H pathogens) IL-12 IL-4 Th2 Eosinophils (helminth IL-4? IL-5 infections) & Mast cells IL-13 All T helper cells activate B cells to (Allergy) produce antibodies IL-23 Th17 IL-17 IL-22 Neutrophils (extracellular RCSI LEADING 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 Virally infected cell will display viral antigens on MHC class I molecule Activated cytotoxic T cells bind CTL T H E W O R L D T O B E T T E R H E A LT H antigen on MHC class I Packed full of vesicles with toxic enzymes for killing Released once CTL is activated – Perforin forms pores in membrane – Granzymes activate apoptosis RCSI LEADING They don’t kill pathogens, they kill cells infected by pathogens!!! Dr Chiara De Santi, Adaptive Immunity T cells  HOMEOSTASIS As the antigen is cleared, 90% of effector T cells die by apoptosis T cells are deprived of activation signals T H E W O R L D T O B E T T E R H E A LT H (antigen, CD28 and IL-2 all decrease) Inhibitory pathways are activated (eg. CTLA-4 and PD-1 are CD28 family members which inhibit the second signal in T cell activation) T regulatory cells (Treg) can dampen CD4 and CD8 T cell responses RCSI LEADING Dr Chiara De Santi, T cell Biology - BHI-16  LIFE CYCLE OF A T CELL T cell Development T cell Activation T cell Effector Function Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H CD8+ T cells KILLING (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and macrophag PRIOR TO INITIAL es and ANTIGEN EXPOSURE ANTIGEN EXPOSURE Antibody other productio immune RCSI LEADING n cells RESPONSE TO RECOGNISED ANTIGEN Dr Chiara De Santi, T cell Biology - BHI-16  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 Menti meter B. Th2 code: 5706 0027 T H E W O R L D T O B E T T E R H E A LT H C. Th17 D. Treg Which of the following cytokines do Th2 secrete? Menti meter A. IL-5 B. INF-γ code: C. IL-17 6804 5247 D. IL-8 Which cells are mostly activated by Th2? RCSI LEADING A. Macrophages B. Neutrophils Menti meter C. Eosinophils code: 1801 8924 Dr D. Dendritic cells Chiara De Santi, Adaptive Immunity T cells  DISORDERS ASSOCIATED WITH T T H E W O R L D T O B E T T E R H E A LT H CELL DYSFUNCTION RCSI LEADING Dr Chiara De Santi, Adaptive Immunity T cells  AUTOIMMUNITY AND IMMUNE TOLERANCE Self-tolerance  unresponsiveness of T cells to self antigens (prevents autoimmunity). It is achieved through:  Central Tolerance  in the thymus T H E W O R L D T O B E T T E R H E A LT H (‘central’ or primary lymphoid organ), it eliminates most of auto-reactive T cells (negative selection)  Peripheral Tolerance  in peripheral tissues, it eliminates T cells which recognise self-antigens not expressed in the thymus When tolerance fails  auto-reactive T RCSI LEADING cells recognise self-antigens  autoimmunity  autoimmune disorders (such as multiple sclerosis, rheumatoid arthritis, IBD etc) Dr Chiara De Santi, T cell Biology - BHI-16  T cell Immunodeficiencies 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 T H E W O R L D T O B E T T E R H E A LT H 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  RCSI LEADING low/absent T/B cells Typically fatal in first 2 years of life, with severe bacterial, viral and fungal infections C Examples: Dr X-linked severe SCID (most common hiara De Santi, T cell Biology - BHI-16  SUMMARY T cell Maturation T cell Activation T cell Effector Function Thymus Lymph Nodes Peripheral Tissue (primary lymphoid tissue)(secondary lymphoid tissue) (any tissue) Direct T H E W O R L D T O B E T T E R H E A LT H KILLING CD8+ T cells (Cytotoxic) CD4+ T cells Immature (Helper) T cells HELP given to B cells and TCR rearrangement T cell is ACTIVATED macrophag Selection process Clonal expansion of es Differentiation into antigen specific Antibody CD4/CD8 lineage clone productio RCSI LEADING n Now known as Naïve T Differentiation into cells Effector cell Dr Chiara De Santi, Adaptive Immunity T cells