Adaptive Sensing

• Sensing microorganisms


  1. Adaptive sensing to clear infection

  2. Immune system first needs to detect infection
• Innate and Adaptive immunity

  • Use two different receptor systems to see pathogens
  • Both systems have advantages and disadvantages
  • The systems work together to detect infection
• The Immune Detection Challenge

  • How can you rapidly detect such a wide range of diverse pathogens?
  • How can you individually recognise specific pathogens?
  • How can you remember previous pathogen encounters?
• The Immune Detection Solution

  Two interwoven detection systems: Innate and adaptive immunity see pathogens in different ways
• Pattern-recognition receptors (PRRs)


  • Rapid recognition of infection and broad classes of microbes
  • Not adaptable, not very specific, no memory
• Adaptive Immunity


  • Can recognise almost any microbial or non-microbial molecule (antigens) with a high degree of specificity
  • Very large (almost infinite) receptor diversity
  • Adaptable; receptors created by somatic recombination of gene segments
  • Each cell has one unique receptor that is highly specific for a particular antigen
• Antigen


  A molecule recognised by adaptive immune cells, will bind either a T cell receptor or antibody (B cell receptor), or both
• Epitope


  The precise part of the antigen recognised by the T or B cell receptor. An antigen can have multiple epitopes.
• Paratope


  The part of the antibody or T cell receptor that binds the epitope
• Cells of adaptive immune system

  • T cells only recognise Ag presented to them by professional Antigen Presenting Cells (APC), e.g. macrophage or DC
  • B cells recognise Ag on its own
  • T and B cells recognise Antigens in different ways
• T cell Antigen Receptor

  Only membrane bound, called T cell Receptor (TCR)
• B cell Antigen Receptor

  • Membrane bound and secreted
  • Secreted form has immune effector functions, called Antibody (Ab) or Immunoglobulin (Ig)
  • Membrane form called B cell Receptor (BCR) or surface Immunoglobulin (sIg)
  • Surface receptors allow the cell to recognise antigens
• T cell Ag


  • Linear peptide (amino acid) sequence, 8-25 amino acids long
  • Presented by an antigen presenting cell
  • Proteins have to be broken down into peptides
  • An 8aa sequence has 7.8e10 permutations and a 25aa sequence has 8.8e34 permutations, enough to uniquely identify proteins from any microbe
• B cell Ag


  • Conformational (can be linear)
  • Epitope can cross loops (discontinuous)
  • Native molecule
• Antibody structure


  Fc region defines effector functions
• T cell receptor


  • Also consists of two chains, alpha chain and beta chain
  • T cell receptor has one Ag binding site, antibodies have two Ag binding sites
• Antigen binding domains are modular


  Light chain is equivalent to TCR-α chain, Heavy chain is equivalent to TCR-β chain
• Antigen Receptors are created by Somatic Recombination


  1. Antigen binding domains are modular

  2. VDJ recombinase

  3. Chromosome 14
• Antigen Receptors are created by Somatic Recombination


  VDJ recombinase is used to recombine the different gene segments
• Junctional diversity


  • Rearrangement of V, D and J genes gives a few million antibody specificities, good but not enough
  • Need other ways of increasing diversity
• Junctional diversity


  Rearrangement of V, D and J genes gives a few million antibody specificities. Good, but not enough. Need other ways of increasing diversity
• Junctional diversity


  1. Joining of v, d, and J not always precise

  2. RSSs (Recombination signal sequences) are used to align V, D, and J segments

  3. Addition of bases

  4. Creation of P- nucleotides

  5. Random addition of N- nucleotides

  6. Terminal deoxyribonucleotidyl transferase (TdT)

  7. Deletion of bases

  8. A new DNA sequence at borders between V, D, and J regions

  9. Changes amino acid sequence

  10. Fill in the gaps

  11. Sequence aligns
• Productive vs non-productive rearrangements

  • The majority of rearrangements will not result in functional protein
  • Only B cells that produce a functional rearrangement survive, those that do not die via apoptosis
• • 2x chromosome 14 (one from each parent), so 2 sets of V, D, J genes
  • 2 chances to make a productive rearrangement for each chain
  • Each B cell specific for one Ag
  • Only one Ab (B cell Receptor) allowed per cell
  • A successfully rearranged chain will block gene rearrangement on the other chromosome (allelic exclusion)
• • 3 billion B cells in human body
  • 300 billion T cells in human body
  • Each with a unique antigen receptor
  • Each with a different specificity
  • Hugely diverse B and T cell populations allowing us to recognise and respond to any invader
  • But, the number of T and B cells able to respond to any one antigen is very low (e.g. only 30 B cells in human able to respond to any one antigen)
• Clonal expansion


  1. T/B cell sees its Ag and becomes activated

  2. Activated T/B cells divide

  3. All daughter cells have identical Ag specificity

  4. The time required to activate and expand Ag-specific T/B cells to an effective number makes adaptive response slow

  5. IL-2 (cytokine) drives T cell clonal expansion
• Immune Evasion: Antigenic variation


  • Influenza Surface proteins: Haemagglutinin and neuraminidase
  • HIV High mutation rate
  • Antigenic variation occurs in the host
  • Prevents effective adaptive immunity
  • Very difficult to develop vaccines
  • Trypanosomes & malaria Switch between multiple versions of same molecule
• • Somatic recombination of V, D and J genes allows the creation of T cell receptors and antibody (B cell receptors) that can recognise almost any protein or organic molecule
  • This is also adaptive immunity's Achilles heel
• • Almost any protein or organic molecule... We're made of proteins and organic molecules!! So is food and many other innocuous molecules we are exposed to!!
  • Pollen
  • 8 main food allergens
  • Dust mite
  • Type 1 diabetes
  • Multiple sclerosis
  • Rheumatoid arthritis
  • T and B cells cannot tell what they are recognising
• Central Tolerance


  • A mechanism by which T and B cells capable of recognising self antigens are deleted before they are released systemically to fight infection
  • Self-reactive T cells removed in thymus
  • Self-reactive B cells removed in bone marrow
  • Most potentially dangerous self-reactive T cells are deleted before they can cause damage, but this process is not perfect
  • Also, does not remove T cells that can recognise innocuous Antigens such as in food
• Advantages of Adaptive Sensing

  • Very adaptable, somatic rearrangement of gene segments allows the creation of receptors that can recognise almost any possible antigen
  • Highly specific, having a receptor that can identify a particular species or strain of microbe allows you to remember that microbe
• Disadvantages of Adaptive Sensing

  • Slow, requires time to activate and clonally expand cells with relevant receptor
  • High specificity means it is relatively easy for a microbe to evade recognition by changing its antigenic structures
  • Receptor cannot tell what it is recognising and cannot distinguish pathogens from self or innocuous molecules (e.g. pollen)
• • A match made in heaven
  • Innate Immunity: Not very specific, but can identify whether something is a pathogen
  • Dendritic Cell
  • T cell: Very specific, but cannot tell what it is recognising
  • Adaptive Immunity
  • Immune Sensing 3: Linking innate and adaptive immunity