Adaptive

• The adaptive immune response develops when the innate response is overwhelmed and often determines the outcome of an infection.
• Adaptive immunity takes from days to weeks to develop as it is a specific response to a pathogen.
• The receptors for the adaptive immune response are formed following gene rearrangement in somatic cells. There are a huge number and they are highly specific so these receptors can distinguish between very closely related epitopes.
• Adaptive immunity


  Develops in response to pathogen exposure, specific to pathogen
• Antigen receptors are receptors on lymphocytes that bind to specific antigens
• Lymphocytes

  • B-lymphocytes (B-cells) have membrane-bound immunoglobulins as B-cell receptors
  • T-lymphocytes (T-cells) have T-cell receptors that recognise antigens displayed by MHC molecules
• Lymphocytes have a diverse antigen binding repertoire due to gene rearrangement, each lymphocyte has a unique antigen receptor
• Gene rearrangement in B-cells


  1. DNA of undifferentiated B cell has multiple V, J, and C gene segments

  2. Recombinase links V and J segments, deleting DNA in between

  3. Transcription of permanently rearranged gene

  4. Translation into light chain of antigen receptor
• Lymphocyte states

  • Naïve lymphocytes (have not encountered antigen)
  • Activated lymphocytes (stimulated by antigen)
  • Effector lymphocytes (B-cells differentiate to plasma cells, T-cells form cell mediated immunity)
  • Memory lymphocytes (important for subsequent encounters)
• Activation of naïve T-cells

  • Naïve T-cells activated by antigen presenting cells (APCs) like dendritic cells
  • Interaction with MHC-peptide complex through TCR and CD4/CD8, co-stimulatory molecules on APCs interact with CD28 on T-cell
• B-Lymphocyte receptors are specific to pathogens and their products. They recruit immune cells and other molecules as well as secreting antibodies.
• IgG has two heavy chains and two light chains with an effector function defined by the heavy chain.
• The variable region of a B cell receptor is where an antigen will bind.
• The constant region of a B cell receptor has an effector function and is the transmembrane anchor.
• T cell receptors recognise antigens displayed by Major Histocompatibility (MHC) molecules on cells. The receptor has two polypeptide chains.
• Most T-cells have a receptor consisting of α- chains and β-chains linked by disulphide bonds (αβ-Tcells). Some T-cells have a receptor consisting of γ- chains and δ-chains (γδ T-cells) which seem to be a larger proportion of T-cells in some animal species.
• Differences in lymphocyte receptors:

  A) Two

  B) One

  C) antibodies

  D) plasma

  E) cells

  F) Not secreted

  G) directly

  H) intact antigen

  I) amino acid

  J) MHC

  K) peptide

  L) MHC

  
• B-cells are activated with the help of T helper cells and/or through binding with the antigen.
• B-cell co-receptors include CD19, CD21 and CD81. Antigen dependent signalling is enhanced if co-receptors are also bound.
• T-cells recognize antigens displayed on cell surface.
• Pathogen peptides are processed in the T cell which are presented on the cell surface by MHC molecules. T-cell receptors interact with MHC-peptide complexes via antigen receptors.
• Naïve T-cells must be activated by antigen presenting cells (APCs) such as dendritic cells.
• The activation of naïve T-cells occurs through interaction with MHC-peptide complexes through the T cell receptor and CD4 or CD8 co-receptors. Co-stimulatory molecules are expressed on specialised antibody producing cells which interact with CD28 receptors on the T-cell.
• Class I Major Histocompatibility:

  • Highly polymorphic binding cleft
  • Bind short peptides (8-10aa)
  • Binds CD8 T-cells (cytotoxic T-cells)
  • Expressed on most nucleated cells (variable expression)
• Class II Major Histocompatibility:

  • Highly polymorphic binding cleft
  • Can bind longer peptides
  • Binds CD4 T-cells (helper T-cells)
  • Expressed on specialised antigen presenting cells and other immune cells ( DCs, macrophages, B-cells)
• Class I MHC:

  • Utilises peptides from cytosol transported to ER
  • E.g. Viruses and some bacteria that replicate in cytosol
  • Presented on MHC class I of infected cell
  • Detected and eliminated by CD8 cytotoxic T-cells
• Class II MHC:

  • Utilises peptides from proteins degraded in endosomal vesicles
  • E.g. Pathogens replicating in endosomal vesicles or extracellular pathogens internalised following phagocytosis
  • Presented on MHC Class II of immune cell • Detected by CD4 T-cells (helper) which assist in pathogen elimination • Macrophage activation • B-cell activation
• Class II MHC:

  • Utilises peptides from proteins degraded in endosomal vesicles
  • E.g. Pathogens replicating in endosomal vesicles or extracellular pathogens internalised following phagocytosis
  • Presented on MHC Class II of immune cell
  • Detected by CD4 T-cells (helper) which assist in pathogen elimination
  • Macrophage activation
  • B-cell activation
• Lymphocytes are generated in the lymphoid tissues. Bone marrow creates B-cells and the thymus creates T-cells. The cells migrate to peripheral lymphoid tissues such as the lymph nodes, spleen and mucosal lymphoid tissue.
• B-lymphocytes generate in the bone marrow. A receptor VDJ gene rearrangement and assembly of an antigen receptor occurs as the cell matures.
• Immature B-cells are tested for reactivity to self antigens through negative selection or central tolerance. Self-reactive B-cells that escape may be removed in periphery tissues by peripheral tolerance.
• B cells migrate within the bone marrow as they mature from the endosteum towards the central sinus of bone marrow. The final stages of development occur in peripheral lymphoid tissues.
• T-lymphocyte progenitors migrate from bone marrow to the thymus where they mature. Receptor gene rearrangement and assembly of antigen receptor occurs and rearrangement does not stop until there is a positive selection following interaction with the MHC complex.
• Lineage decisions for T cells occur in the thymus. Early commitment of double negative cells to δγ migrate to the periphery without positive or negative selection. Positive selection occurs after an interaction of antigen receptors and co-receptors with MHC on the thymus epithelial cells. Negative selection of T-cells with strong interactions with self peptides on the MHC on APCs in thymus.
• Most T cell development occurs in the cortex, only mature single positive cells travel into the medulla.
• Naïve T-cells circulating in peripheral blood and lymphatics are activated once it encounters antigens presented on the MHC by antigen presenting cells in peripheral lymphoid tissue e.g. lymph nodes and differentiate into effector T-cells.
• Naïve T Cell Activation:

  A) specific for antigen

  B) migrated from site of infection

  C) MHC of dendritic cells

  D) Recognition

  E) antigen producing cells

  F) differentiation

  G) effector

  H) no longer required

  
• After clonal expansion differentiation, effector T-cells migrate out of lymphoid tissues back into the blood, then migrate into the tissues. T cells begin searching for target cells with MHC “antigen of interest” complex on the surface. If it finds its target cell then it binds more tightly so that can release effector molecules.
• Naïve B-cells are difficult to activate through antigen contact with BCR alone, which occurs in lymphoid follicles.
• Antigen specific B-cells come into contact with the antigen. B-cells display antigens on MHC Class II to activate corresponding T-cells.