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Time Course of the Primary Immune Response

Time Course of the Primary Immune Response. Innate immunity. Acquired immunity. Ig Maturation. Journey of a B Cell. Contact Between the TCR and MHC/peptide: Not All Peptides are Created Equal. The Two-Signal Theory of T-cell Activation. 2. 1. 1. 2. No response or Anergy. Activation.

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Time Course of the Primary Immune Response

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  1. Time Course of thePrimary Immune Response Innate immunity Acquired immunity

  2. Ig Maturation

  3. Journey of a B Cell

  4. Contact Between the TCR and MHC/peptide:Not All Peptides are Created Equal

  5. The Two-Signal Theory of T-cell Activation 2 1 1 2 No response or Anergy Activation No response APC = Antigen-presenting cells TCR = T-cell receptor for antigen DC = Dendritic cell CD80 = Co-stimulatory receptor

  6. Two Major Functional T Cell Subsets CD4+ T cell CD8+ T cell z z z z g g d d e e Lck Lck CD3 CD3 C C a b C C a b TCR TCR V CD4 b V b V a V a CD8 peptide peptide MHC I MHC II APC APC (1) Interacts with MHC class II expressing cells (APCs) (2) Helps B cells to synthesize antibody (3) Induces and activates macrophages (4) Secretes cytokines (1) Interacts with MHC class I-expressing cells (all nucleated cells) (2) Kill MHC class I-expressing target cells (3) Secretes cytokines

  7. CD4+ T Cells Activate Macrophages and B cells

  8. Regulation of the Immune Response:a Conceptual View Immunity Tolerance Activation Suppression

  9. Regulation of the Immune Response:a Conceptual View AutoimmunityImmunodeficiency Immunity Tolerance Activation Suppression

  10. Regulation of the Immune Response:a Conceptual View AutoimmunityImmunodeficiency Immunity Tolerance Activation Suppression

  11. Antibodies: Secreted or Transmembrane TCR: Transmembrane

  12. Figure 4-2 DNA Rearrangement RemovesSequences Between V, D and J Segments RNA Splicing Removes Sequences Between J and C Segments DNA RNA

  13. Antigen-Independent B-Cell Development Bone Marrow • DNA rearrangements establish the primary repertoire, creating diversity 2. Allelic exclusion ensures that each clone expresses a single antibody on the surface, establishing specificity 3. Deletion of self-reactive clones establishes tolerance

  14. THE B CELL RECEPTOR Bound antigen is inter- nalized and presented to T cells. 2. Bound antigen gives signals to the B cell to proliferate and differentiate.

  15. Signalling from the BCR Lack of Btk causes Bruton’s X-linked agammaglobulinemia (blocked at pre-B stage)

  16. Antigen-Dependent B Cell Development In Periphery (spleen and LN) Antigen and TH cells give B cells two signals: 1) proliferate 2) differentiate T-cell dependent responses are refined two ways: 1) higher affinity antibodies 2) IgG/A/E (“switched”) isotypes Two products of B cell development: 1) plasma cells secrete Ig (final effector) 2) memory cells respond to IIo antigen

  17. T Cell-B Cell Communication (B cells signal T cells by presenting Ag in association with MHC II) T cells provide 2 kinds of help to B cells: Cell-cell signals from CD40L/CD40 and other surface molecules. 2. Secreted cytokines

  18. The Germinal Center Affinity maturation a. Somatic hypermutation b. Selection for high affinity clones 2. Isotype switch recombination 3. Peripheral tolerance 4. Final maturation to memory or plasma cell.

  19. T help and no Ag (eliminates low affinity clones) or Ag and no T help (eliminates self-reactive clones, giving tolerance) AFFINITY MATURATION IN THE GC Dark zone + Somatic Hypermutation Proliferation (Iterative cycles) Light zone Ag(FDC) + T cell help SURVIVAL but DEATH

  20. 1. Memory B cells Surface Ig, usually IgG High affinity for antigen Long-lived, even in the absence of antigen Respond rapidly to secondary stimulation 2. Plasma Cells Secrete copious amounts of Ig, no surface Ig Non-dividing Some are short-lived, some become long-lived in the bone marrow

  21. Secreted Antibodies Function in Various Ways To Eliminate Foreign Invaders

  22. How T cells recognize antigen Notion of immunological “SELF” Skin graft transplantation compatibility • Rejection by adaptive immune system T cell response • Graft compatibility genetically determined Extremely polymorphic trait -many alleles Governed by genes of major histocompatibility complex (MHC) that encode MHC molecules, the principal targets of rejection Differences in MHC molecules between individuals are central to determining “SELF”

  23. (Self-peptides are used as a surrogate for foreign peptides since there are few non-self peptides) *** The selection process (Thymic “education”) has two stages • First stage selects clones capable of recognizing self peptide in an individual’s own MHC molecules - positive selection • Second stage eliminates overtly self reactive clones with high affinity for self peptide:MHC- negative selection

  24. Polymorphic residues of MHC The TCR repertoire differs from individual to individual • The specificity of self/non-self peptide binding to MHC molecules determined by pockets that only bind certain amino acid side chains • MHC genes are extremely polymorphic and alleles encode pockets with specificities for different amino acid side chains The TCR is specific for both peptide and MHC- A complex ligand The definition of immunologic self is made by selecting the clonal T cell repertoire on self-peptides bound to the individual’s particular allelic forms of MHC molecules

  25. The immune system makes this distinction by loading and recognizing peptides in either class I or class II MHC Cytosolic Virus or Pathogen Ingested Bacteria or Endocytic Pathogen Extracellular Pathogen or Toxin Challenge: Presenting cell: Any cell Macrophage/DC B cell Cytosol MHC class I CD8 T cells Death of cell presenting the viral antigen Endocytic vesicles MHC class II(or I) CD4 T cells (or CD8) Activation of cell to enhance pathogen killing Peptide degraded in: Peptides bind to: Presented to: Effect on presenting cell of T cell recognition: Endocytic vesicles MHC class II CD4 T cells Provision of help to B cell for production of antibodies

  26. a1 a2 N Structure of peptide-binding class I MHC domain

  27. Codominant expression of MHC alleles a=paternal haplotype b=paternal haplotype c=maternal haplotype d=maternal haplotype a/b c/d a/d b/c a/c b/d

  28. Polymorphic amino acids that distinguish alleles of MHC class I molecules are found primarily in pockets that determine peptide binding or on the surface that interacts with the TCR

  29. Because the TCR recognizes both peptide and MHC molecule, T cell recognition of MHC-peptide is both MHC restricted and specific for the immunizing peptide T cell T cell T cell Peptide from virus X Peptide from virus Y Peptide from virus X HLA- B7 HLA- B27 HLA- B7 APC APC APC Yes No No Target killed: In each of the 3 experiments the T cell is from a HLA-B7 person who recovered from infection by virus “X”. The APC target cell is either infected with virus X or Y and is from an individual who is either HLA-B7 or HLA-B27

  30. TCR repertoire selection and thymocyte differentiation into CD4+ or CD8+ T cells 5% 80% CD8 Staining CD4-CD8+ CD4+CD8+ 3% 12% CD4-CD8- CD4+CD8- CD4 Staining

  31. Implications of Positive/Negative Selection • Individuals with different MHCs have different TCR repertoires • T cells mature into CD4 or CD8 single-positive cells as a result of positive selection.

  32. Key molecular interactions between T cells and APCs MHC class II/ autopeptide CD3 TCR CD40 CD80 Activated T cell CD40 CD40L CD40 CD28 CD80 MHC class II (1) induction of cytokines/chemokines (IL-8, IL-12, TNF-a, MIP-1a) (2) stimulation of CD80 and CD86 expression and co-stimulatory function with activation of T cell growth (3) augmentation of antigen-presenting function

  33. Naïve CD4+ T cells differentiate into Th1 and Th2 subsets Th1 Cells IL-2IFN-g TNF IL-2 IFN-g, IL-12 Antigen + APC IFN-g (–) IL-4 IL-10 (–) Resting CD4+ cell “pTh” Activated CD4+ cell IL-4 IL-5 IL-6 IL-10 IL-4, IL-13 Th2 Cells

  34. Functions of T helper subsets Functions of Th1 subsets Th1 Cells • Activate macrophages/dendritic cells augment antigen presentation • induce delayed type hypersensitivity (DTH) responses important in eradicating intracellular pathogens (TB, leprosy, listeria • mediate Th1 diseases (ie; rheumatoid arthritis, multiple sclerosis and type I diabetes IL-2IFN-g TNF IL-4 IL-10 (–) IFN-g (–) Functions of Th2 subsets IL-4 IL-5 IL-6 IL-10 • Help B cells and induce humoral immunity • mediate allergic and immediate hypersensitivity responses • involved in antibody mediated immune diseases like SLE and ITP Th2 Cells

  35. Antigen Processing and Presentation by B cells ANTIGEN MHC Class ll BCR (SmIg) B cell Peptide Internalization of antigen/Ig Antigenic peptides bind to MHC class II molecules Antigen binds specifically to BCR (surface membrane Ig), is internalized into vesicles and cleaved into peptides which displace and bind to MHC class II molecules. The peptide/MHC complex is then transported to the surface membrane.

  36. T Cell- Macrophage Interactions Fc receptor TCR a,b MHC class II CD3 CD4 CD4 Th1 Cell Macrophage CD28 B7 (CD80) IL-2 IL-1 IL-6 IL-12 TNF TGF-b IL-12 CD40L CD80 TCR a,b CD4 IL-2 IFN-g Receptor cytotoxic granules CD80 CD28 MHC II Activated Macrophage Activated Th1 Cell

  37. Maximum number of different types of HLA molecules expressed on the cell surface Nucleated cells Antigen presenting cells Class I (HLA-A) Class I (HLA-B) Class I (HLA-C) Class II (HLA-DR) Class II (HLA-DQ) Class II (HLA-DP) Total 2 2 2 0 0 0 6 2 2 2 2 4 4 16 (actually more) Each of these MHC molecules selects its own T cell repertoire that only recognizes peptides presented by that particular type of MHC molecule

  38. Type I & II Cytokine Receptors (Hematopoietin R.) Toll (TLR) /IL-1 Receptors TNF Related Receptors TGF-b Receptors Chemokine Receptors V. Cytokines you need to know • IL-2 (big family e.g. IL-7 & IL-15) • IL-4 (small family inc. IL-13) • IL-6 (large family inc. G-CSF) • IL-10 (growing family) • IL-12 (small family inc. IL-23) • IFN-g • IFN-a (large family) • IL-1 • IL-18 • LT-a • TNF-a • CD40L • FasL • TGF-b (very large family) • Chemokines (see Fig. 11.6) • Inflammatory • Non-inflammatory • Innate Adaptive • √√ • √√ • √√ √ • √√ √√ • √√ √ • √√ √√ • √√ • √√ • √√ √ • √ √√ • √√ • √ √√ • √√ √√ • √√ √√ • √√ √√ • √√ √√ See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas

  39. Type I & II Cytokine Receptors (Hematopoietin R.) Toll (TLR) /IL-1 Receptors TNF Related Receptors TGF-b Receptors Chemokine Receptors V. Cytokines you need to know • IL-2 (big family e.g. IL-7 & IL-15) • IL-4 (small family inc. IL-13) • IL-6 (large family inc. G-CSF) • IL-10 (growing family) • IL-12 (small family inc. IL-23) • IFN-g • IFN-a (large family) • IL-1 • IL-18 • LT-a • TNF-a • CD40L • FasL • TGF-b (very large family) • Chemokines (see Fig. 11.6) • Inflammatory • Non-inflammatory • Innate Adaptive • √√ • √√ • √√ √ • √√ √√ • √√ √ • √√ √√ • √√ • √√ • √√ √ • √ √√ • √√ • √ √√ • √√ √√ • √√ √√ • √√ √√ • √√ √√ See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas

  40. IL-2 activates T-cells in an autocrine manner

  41. VIII. Chemokines • Important chemoattractants • Regulate steady state and inflammatory leukocyte traffic • Signal through G-protein coupled receptors • Therefore good drug targets for big Pharma • Two chemokine receptors serve as co-recpetors for HIV infection (CXCR4 and CCR5)

  42. Question: How do viruses that don’t infect “professional APCs” such as dendritic cells elicit a primary immune response? After all, virally-infected cells don’t normally traffic to 2˚ lymphoid organs

  43. “Classic” view of CTL response against virus-infected cells PVR expressed on non-hematopoietic cells. Endocytosis of virus, nuclear entry, synthesis of viral proteins in cytosol. Infection with Poliovirus Presentation of viral peptides on MHC Class I to CD8+ cytotoxic T-cells Proliferation of cytotoxic T-cells (CTLs) Perforin/granzyme- mediated cell death Cross-priming of exogenous antigens by dendritic cells • Phagosome-to-cytosol protein export; ubiquitin-mediated proteolysis of viral proteins; Presentation of peptide via MHC Class I Perforin/granzyme- mediated cell death of DC; proliferation of CD8+ CTL; Killing of virus-infected epithelial cells by CTL Cytopathic changes; recognition and phagocytosis by dendritic cell PVR expressed on non-hematopoietic cells. Infection with Poliovirus

  44. Why do NK Cells Fail to Recognize Healthy Cells?

  45. Summary 1. For cytotoxic CD8 T-cells, ligation of the TCR by MHC I/peptide + co-stimulation results in release of granzymes and perforin and/or FasL, leading to apoptosis of the target cells. 2. Viruses evade host defense, in part, by down-regulating MHC Class I. Uninfected dendritic cells circumvent this by “cross-priming”: phagocytosis of virus-infected cell and presentation of “exogenous” viral antigens on MHC Class I. 3. The innate immune system has a rapid onset and recognizes molecular patterns in a non-clonal fashion. 4. NK cells lack TCRs, but instead express both activating and inhibitory (e.g., KIRs) receptors at their surfaces. The relative expression and ligation of these receptors determines the outcome (i.e., killing or not) of the NK effector response. 5. Innate immune B-cells (e.g., B-1 cells and marginal zone B cells) recognize carbohydrate antigens, secrete IgM, and are not long-lived. 6. Innate immune T-cells (gd T-cells, and NK T cells) recognize non-peptide antigens in non-classical MHC-like molecules. They mediate cytotoxicity & rapid cytokine secretion.

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