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The adaptive immunity and its features..
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- 2. Objectives: • Why adaptiveimmune system? • Self/non-self discrimination: Significance • Mediators of adaptive immunity • Cell-mediated versus humoral immunity • T and B cell activation • Immunological memory • Adaptive versus innate immunity
- 3. Why adaptive immunity? •Shortcomings of innate immunity: – Non-specific • Similar pattern of response for all pathogens – Poor regulation • Control mechanisms are poor or lacking – Poor amplification • Response magnitude same for all insults – Lack of self discrimination • Harm to self results for lack of specificity – Short duration – No memory
- 4. The enemies aredifferent….. FUNGUS -Epidermophyton floccosum (causes athlete’s foot) VIRUS- Polio BACTERIA -Clostridium difficile (causes antibiotic- associated colitis & diarrhea) PARASITE - Tapeworm
- 5. ….therefore the responsesmust be tailored to specific enemies. •Successful immune response is a huge investment!! You need to a way to remake it: ➔ Faster ➔ Larger ➔ More specific ➔ Less damage to self
- 6. Specific (Adaptive) Immunity •Lymphocytes – – – pluripotent stem cells... B Cells (bone marrow) T Cells (thymus) • Antigen: a foreign molecule that elicits a response by lymphocytes (virus, bacteria, fungus, protozoa, parasitic worms) Antibodies: antigen-binding immunoglobulin, produced by B cells Antigen receptors: plasma membrane receptors on B and T cells • •
- 7. Principles of AdaptiveImmune Responses • Specific recognition of individual antigens by immune cells via antigen receptors • Clonal selection and expansion occurring after antigenic recognition- PRIMARY IMMUNITY – Generation of effector T cells and B cells • Later exposure to the same antigen: SECONDARY (MEMORY) RESPONSE – Rapid proliferation of memory cells
- 8. Q uickTime™anda TIFF(Uncompressed)decompressor areneededtoseethispicture. Clonal Selection ofLymphocytes • Lymphocytes are made randomly – Not directed by antigens Each lymphocyte bears a specific receptor Varied receptor specificity due to rearrangement of genes Antigen “selects” appropriate lymphocytes “Selected” cell undergoes clonal expansion Expansion produces clones of effector and memory cells • • • • •
- 9. • Each antigen,by binding to specific receptors, selectively activates a tiny fraction of cells from the body’s diverse pool of lymphocytes. • This relatively small number of selected cells gives rise to clones of thousands of cells, all specific for and dedicated to eliminating the antigen.” • At the end of the response, a population of the expanded cells (memory) persists and are mobilized faster during subsequent encounter – Frequency of memory cells several others of magnitude higher than naïve cells Summary of clonal selection
- 10. Self/non-self discrimination • Propertyof the adaptive immune system to mount specific/targeted responses to foreign antigens without harming self • Achieved via early and continuous presence of self-antigens • Important for self tolerance and control of autoimmunity • Can be broken under certain conditions
- 11. Self Tolerance • CentralTolerance (primary): – Deletion of cells that recognize self antigen in primary lymphoid organs • Peripheral Tolerance (secondary): – Deletion or anergy of cells that recognize self antigens in the peripheral tissues – Regulatory mechanisms also involved • Failure of tolerance results in autoimmune diseases
- 12. Significance of Self/non-self discrimination •Prevention of autoimmunity • Scarce resources are all directed against “potential” enemies • What is the price for self discrimination?? • Why do we develop autoimmune diseases anyway?
- 13. Mediators of AdaptiveImmune Response • Highly dependent on T and B cells bearing specific receptors – T cell receptors – Membrane immunoglobulin on B cells • Antigen presenting cells (APCs) – Macrophages, Dendritic cells, B cells
- 14. Types of Adaptiveimmunity • Cell-mediated immunity: Immunity mediated by T cells via: – Direct lysis of target (infected) cells – Production of cytokines that activate infected cells to kill pathogens • Humoral immunity: mediated by antibodies produced by B cells – Antibodies bind to whole or fractions of antigens outside cells
- 15. Division of Labor,yet cooperative!! • T cells mediate cellular immunity: – Control of intracellular pathogens – Control of tumors • B cells mediate Humoral immunity: – Control of extracellular pathogens – Mediates allergy and hypersensitivity • T and B cells cooperate for effective immunity – T cell help may be needed for B cell activation and B cells may present Ag to T cells
- 16. T cells • 70%of lymphocytes in peripheral blood • Lymphoid progenitor in bone marrow • Maturation in the thymus – Positive and negative selection – Absent in nude (athymic) and SCID mice • T cell receptor complex • T cell types • MHC restriction • Function: T cells mediate cellular immunity
- 17. The thymus isimportant for T cell development • Athymic mice (nude) and humans (DiGeorge syndrome) are immunodeficient due to lack of T cells
- 18. MHC Molecules • Majorhistocompatibility antigen – Body cell surface proteins coded by a family of highly polymorphic genes – MHC class I: found on all nucleated cells – MHC class II: found only on APCs • T cell receptors recognize antigenic peptide/MHC complexes – CD4+ T cells: restricted by class II – CD8+ T cells: restricted by class I
- 19. MHC Restriction: • Propertyof T cells to recognize antigens presented only by self-MHC molecules • Vital aspect of self/non-self discrimination and hence adaptive immunity • A marker of T cell that has been positively selected • Selection occurs in the thymus
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- 21. Types of Tcells • Conventional: – Uses TCR – Helper (CD4+) and cytotoxic (CD8+) T cells – More abundant and highly specific – Restricted by classical MHC (I and II) molecules • Non-conventional: – Uses TCR – Primitive with broad specificity – Restricted by non-classical molecules
- 22. CD4+ T cells •T cells with CD4 marker (glycoprotein) • 70% of T cells in the periphery • T helper cells • Play central role in modulating cellular immunity via secretion of cytokines that modulate: – B cell activation – Immunoglobulin secretion (quality) – Macrophage and dendritic cell activation – Cellular chemotaxis and inflammation • Th1 versus Th2 cells
- 23. Th1 and Th2cells • CD4+ T helper cells can be classified into two based on their cytokine profiles: T helper cell type 1 (Th1) and T helper cell type 2 (Th2). – Cytokine profile is influenced by several factors: • • • • • Nature and dose of antigen Route of infection Initial cytokine environment Type of antigen presenting cell/costimulation Genetic background – The cytokine profile determines the effector function of the helper cell
- 24. Differences b/w Th1and Th2 cells • Th1 cell Produces type 1 cytokines – IL-2, IFN-, TNF-, TNF- Activates macrophages and DCs for intracellular killing of pathogens Mediates CMI • • • Th2 cell Produces type 2 cytokines – IL-4, IL-5, IL-10, IL-13 Provides help to B cells in antibody response Mediates allergy and immunity to extracellular pathogens, including parasites • •
- 25. CD4+ Th1 vs.Th2 cells QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Intracellular pathogens Antibodies for extracellular pathogens and allergy
- 26. Cytotoxic T cells • • • • • Tcells that express CD8 molecule on their surface 30% of T cells in the periphery Destroy cells infected by intracellular pathogens and cancer cells Class I MHC molecules (nucleated body cells) expose foreign proteins TC cell releases perforin and granzymes, proteins that form pores in the target cell membrane; causing cell lysis and/or apoptosis
- 27. • Mediated byB cells • B cell development starts in fetal liver • At birth, bone marrow (mammals) or bursa of fabricius (birds) • B cells produce antibodies (5 classes) – IgM, IgD, IgG, IgA and IgE • Antibody production may/may not depend on T cells Humoral immunity
- 28. Humoral response: Bcells • Stimulated by T-dependent antigens (help from TH cells) APCs with class II MHC proteins process and present antigen to CD4+ T cells (helper cells) Helper T cell become activated Activated T cell secretes cytokines that in turn activate B cell B cell differentiates into effector and memory (plasma) cells and produce antibodies • • • •
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- 30. T CELLS BCELLS Origin: Bone marrow Bone marrow. Maturation: Thymus Bone marrow; Bursa in birds Long-lived Short-lived/long-lived Highly mobile Fairly mobile/stationary No complement receptors Complement receptors No surface Ig Surface immunoglobulins No antibody synthesis Antibody synthesis Effector: cellular & humoral Effector: humoral only COMPARISON OF T CELLS AND B CELLS Reproduced from Brock et al, Biology of microorganisms, 4th ed.
- 31. Antigen presenting cells(APC) • Cells with the capacity to capture, process and present antigenic peptides to T cells • Antigens are presented in the context of MHC class I or II • Also deliver co-stimulatory signal (signal II) to T cells leading to proper activation • Only APCs can activate a naïve T cell – Dendritic cells, Macrophages, B cells
- 32. Dendritic Cell • • • Most potentAPC for naïve T cells Many long membrane extensions Highly variable depending on location – Langerhan cells in the skin – Interdigitaing cells in the thymus – FDC in germinal centers – Veiled cells in lymphatics – Blood dendritic cells in circulation QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
- 33. QuickTime™ and a TIFF(Uncompressed) decompressor are needed to see this picture. Maturation of dendritic cell
- 34. Only mature DCactivates T cells pressor ture. Activation/Proliferation T cell Mature DC Anergy/Apoptosis/ Deletion T cell Immature DC
- 35. Functions of APCs •T cell selection in the thymus (only DCs) • Trap and capture antigen in the periphery • Process antigen into peptides • Store antigens • Transport antigens to peripheral lymphoid tissues • Present antigenic peptides to T cells • Co-stimulate T cells
- 36. T Cell Activation •Requirements: Two signals – Signal 1: specific recognition of antigen (peptide-MHC complex) via antigen receptor – Signal 2: costimulatory signals from APC • Signal 1 alone leads of unresponsiveness – Anergy, Deletion, Apoptosis Q uickT im e™anda T IF F(U ncom pressed)decom pressor areneededtoseethispicture.
- 37. B Cell Activation •Requirements: Antigenic structure determines the rules T cell dependent antigen: – Signal 1: specific recognition of native antigen via receptor • – Antigen processed into peptides and presented to helper T cells via MHC class II – Signal 2: costimulatory signals from helper T cell – Signal 2 results in affinity maturation and isotype switching Q u i c k T i m T I F F ( U n c o m p r e s s e a r e n e e d e d t o s e
- 38. QuickTime™and a TIFF(Uncompressed) decompressor areneeded to see this picture. B Cell Activation contd: • Repeating epitopes e.g. LPG T cell independent antigen: – Repetitive epitopes – Signal 1: specific recognition of native antigen via receptor – Cumulative binding energy enough to trigger activation – No Signal 2 required!! – Poor inducers of affinity maturation and isotype switching ACTIVATION
- 39. Immunological Memory • Abilityof the immune system to respond more rapidly and effectively to pathogens that have been encountered previously – either by previous infection or by vaccination • This reflects the pre-existence of clonally expanded lymphocytes with specificity for the antigen. • Hallmark of adaptive immunity
- 40. Schematic representation ofmemory response (B cell)
- 41. Effectiveness of memory •More responder cells available – Frequency higher than naïve cells More efficient antigen recognition/activation – May not require costimulatory signals for activation Rapid and effective migration to tissues and lymph nodes – Expresses different homing/chemokine receptors than naïve T cells More effective function – Produce qualitatively and quantitatively more cytokines (T cells) or antibodies (B cells) Longer lasting – Naïve cells live for few days/months; memory cells persist for years • • • •
- 42. Maintenance of Memory •Long-lived memory cells persist in the absence of antigen – Experiments with transgenic mice – MHC deficient animals • Memory cells are perpetually stimulated by residual antigen – Antigens trapped for years in FDC (> 35 yr) – Chronic infections (clearance of infection leads to loss of resistance) – Cross-reactive environmental antigens
- 43. Innate versus Adaptiveimmunity Innate Adaptive Receptors Primitive and broad Highly specific (T and B cell receptors) Kinetics Fast (hours-days) Slow (days-wks) Regulation +/- ++++ Amplification No (insignificant) Yes Self discrimination - ++++ Duration Short (days) Long (months/yrs) Memory - ++++
- 44. Innate immunity shapesadaptive immunity Cells of the innate immunity participate in both priming and effector phases of the adaptive immunity – Macrophages and DCs present antigens to T cells – IFN- produced by NK cells can activate macrophages to kill intracellular pathogens – NK cells can directly lyse infected cells Innate immune responses generate molecules (including cytokines) that act as costimulatory (second) signals for T and B cell activation – APCs expresses costimulatory molecules for T cell activation – Production of cytokines (eg IL-1, IL-2, IL-4, IL-10, IL-12, TNF- , IFN-) • •
- 45. The big picture…Integrationof innate and adaptive immunity Courtesy: Abbas and Litchman; Basic Immunology
- 46. Summary • Evolutionary needfor adaptive immunity: – Self/non-self discrimination, specificity, amplification, regulation, duration and memory T and B cells are mediators of adaptive immunity – T cells: cell-mediated immunity – B cells: humoral immunity – Cells of innate immunity also participate (DCs, Macrophages) Activation of T and B cells are different: – T cells: specific recognition of peptide/MHC complex (signal 1) and costimulatory signals by APC (Signal 2) – B cells: recognize native proteins (signal 1). May/may not require signal 2 from CD4+ Th cells (TD and TI antigens) Immunological memory: an important hallmark – Faster and rapid response on a second antigen encounter Innate immune response shapes the adaptive immunity • • • •