Adaptive Immunity

A. Recognizing foreigners: Antigens, epitopes & haptens

  1. There are two basic types of immune responses
    1. Humoral immune response: Antibodies
    2. Cell-mediated immune response: MHC
  2. Specific immunity recognizes foreign material
    1. Antigens: epitopes & haptens
    2. PAMPs
  3. Antigen presenting cells process foreign material:
    1. MHC-I: presentation of internally derived antigens (all nucleated cells, incl. DC, Mɸ, B-cell)
    2. MHC-II: presentation of externally derived antigens (professional APC: DC, Mɸ, B-cell)
  4. Immune system cells have receptors for foreign material:
    1. Toll-like receptors (TLR): peptidoglycan, teichoic acid, LPS, flagellin, ssRNA, dsRNA, DNA, zymosan
    2. T-cell receptors
      • Genetic recombination generates ~ 1015 TCR combinations
      • TCR links to CD3 complex to activate cellular growth & differentiation
      • CD-4 and CD-8 are co-receptors for the TCR
    3. Immunoglobulins
  5. Specific immune responses must be activated
    1. B-cells: Antigen, TH, cytokines, PAMPS, C3d
    2. T-cells: antigen/MHC presentation; coreceptors; cytokines; PAMPs may enhance activation
      • TCR/CD-4 & MHC-II/antigen
      • TCR/CD-8 & MHC-I/antigen
      • CD28 & B7
      • IL-1, 2, 4, 6, 10, 12
    3. NK cells: cytokines, abnormal MHC-I, IgG
    4. Dendritic cells: PAMPS, cytokines
    5. Macrophages (Mɸ): IFN-y; PAMPs
    6. NKT cells: TCR & CD-1
    7. γ/δ T-cells: γ/δ TCR & microbial metabolites

B. Humoral Immunity

  1. B-cell diversity
  2. B-cell differentiation
    1. Naive B-cells (IgD, IgM)Schematic presentation of B cell-T cell activation in the interfollicular, or T cell zone of the spleen, or lymph node Upon interaction with antigen presenting dendritic cells, CD4+ T cells acquire the expression of B cell lymphoma 6 (BCL6), CD28, and CXC-chemokine receptor 5 (CXCR5) to differentiate into early T follicular helper (TFH) cells. These TFH cells migrate to the border of the follicle (due to CXCR5 expression) to interact with FO B cells displaying processed antigen on class II Major Histocompatibility Complex (MHC II). The figure schematically presents internalization of the BCR-bearing antigen, BCR-antigen complex processing in the endosomal vesicle and presentation on MHC II. T cell receptor (TCR)-mediated recognition of peptide antigen displayed on MHC II leads to the expression of CD40 ligand (CD40L) and secretion of interleukin 21 (IL-21) by TFH cell. Engagement of CD40 (expressed by B cell) with CD40L (expressed by T cell) stimulates B cell survival, proliferation (clonal expansion) and differentiation. CD40L-mediated signals in combination with different cytokines secreted by TFH cells (IL-21, IL-10, IL-4) enhance B cell proliferation and also can induce CSR. In turn, the secretion of IL-6 by B cells promote the production of IL-21 by T cell that with extended signaling via TCR upregulates expression of programmed cell death protein 1 (PD1), CXCR5 and inducible T-cell co-stimulator (ICOS). ICOS-ICOS-ligand (ICOSL), CD28-CD86 and PD1-PD1 ligand (PD1L) interactions are necessary for the optimal activation and differentiation of both B and TFH cells. [Reviewed in (Tangye et al., 2013)]. 
    2. B-cell activation
      1. T-cell independent
        • T-independent antigens: peptidoglycan, capsules, flagellin
        • C3d, LPS & cytokines also activate
        • Produces an IgM response
        • No memory cells formed
      2. T-cell dependent
        • T-dependent antigens: proteins
        • Helper T-cells (TH1, TH2, TH3)
          • MHC-II & TCR/CD-4
          • B7 / CD28 and/or CD40 / CD40L
        • Cytokines
    3. Clonal selection
    4. Class switching
      • TH2: switch to IgG, IgA, IgE via IL 4, IL5, IL6
      • TH1: switch to IgG via interferon-γ
      • TH3: promotes IgA production via IL5 & TGF-β
    5. Plasma cells and memory cells
      • Primary Immune response: primarily IgM
      • Secondary Immune response: primarily IgG
    6. Role of cytokines
      • IL-1: activator
      • IL-4, IL-5, IL-6, IFN-g: differentiators
  3. Types of antibodies
    1. IgA - secreted
    2. IgD - membrane-bound
    3. IgE - allergic response; binds to mast cells, basophils
    4. IgG - major secreted plasma Ig; opsonin, complement activation, placental transfer
    5. IgM - pentameric; first responder; plasma; activates complement
  4. Effects of antibodies
    1. Neutralization
      • Adhesins
      • Toxins
      • Viruses
    2. Opsonization
      • Fc receptors - IgG
      • IgE receptors (eosinophils)
    3. Complement activation
      • Classical pathway
      • Ag|Ab complex + C1 --> C2 + C4 --> C3
      • C5a attracts neutrophils
      • C3b enhances opsonization

B. Cell-mediated Immunity

  1. Antigen-presenting cells
    1. Macrophages (MHC-I & MHC-2): secrete IL-1 & IL-6
    2. Dendritic cells (MHC-I, MHC-2, CD-1 glycolipid receptor)
      • iDCs determine type of response: TH1 or TH2
        • TH1 activated by IL-2, IL-12 (macrophage)
        • TH2 activated by IL-4, absence of IL-12/IFN-γ
      • Activation requires co-stimulatory signal (B7/CD28) & cytokines
        • Absence of co-stimulation leads to apoptosis or anergy
    3. B-cells (MHC-II): to TH2 cells
    4. Virus-infected cells, tumor cells, transplant tissue (MHC-1)
  2. T-lymphocytes
    1. Helper T-cells
      • TH1: activates local, inflammatory responses
        • TC and NK cells activated via IL-2
        • B-cell production of IgG & IgM (IL-2, IFN-γ)
        • Macrophage activation (IFN-γ)
        • Inhibition of TH2 responses via IFN-γ
      • TH2: activates later, systemic antibody responses
        • stimulates B-cells via IL-4 & 5; class switching
        • inhibits TH1 response via IL-10
      • TH17: Promotes inflammation even in presence of TGF-b
        • inhibits TH1 and TH2 via TGF-β
        • produces TNF-a, IL-17 (neutrophil activation)
      • Treg: suppress the immune response
        • Suppress TH1 and TH2 via TGF-β and IL-10
        • Promote memory cell formation
    2. Cytotoxic T-cells
      • TCR/antigen
      • CD8 (MHC-1 receptor)
      • CD28 (coreceptor) / B7
      • requires IL-2 for activation
    3. Natural Killer cells
      • CD16 (Fc receptor for IgG): destroy Ig-coated cells
      • MHC-1 receptor (inhibits activity); if inhibitory signal absent, NK destroys cell
        • antigen-independent!
      • activated by IFN α & β, TNF-α, IL-12, IL-2 a.o.
  3. T-cell activation
    1. MHC-1: CD8+ TC cells
    2. MHC-2: CD4+ TH cells
    3. Cytokines
      • Macrophages: IL-1
      • Th cells - IL-2
  4. T-cell responses
    1. CD95/Fas  (apoptosis) pathway: NK, Tc, TH1
    2. Perforins & Granzymes: NK, Tc
    3. IFN-g & TNF-a

C. Immune Responses

  1. T-cell dependent humoral response
  2. T-cell independent humoral response
  3. Cell-mediated immune response

D. Wrap-up: The Superbowl of Immunology

Links and references
  1. http://www.cat.cc.md.us/courses/bio141/lecguide/unit3/intro/t4cell/mhctwo.html
  2. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=imm.section.1722
  3. https://www.researchgate.net/figure/Schematic-presentation-of-B-cell-T-cell-activation-in-the-interfollicular-or-T-cell-zone_fig3_320226448