Sensing Crosstalk

• Sensing


  Linking innate and adaptive immunity to clear infection
• Somatic recombination of V, D and J genes

  1. Junctional Diversity

  2. T cell receptor and Ab (B cell receptor) can recognise almost any protein or organic molecule
• Chromosome 14
• Somatic recombination of V, D and J genes

  1. Hugely diverse T and B cell populations, each cell with unique receptor

  2. A T or B cell that recognises Ag and becomes activated proliferates to create a clonal population all with same receptor and so all specific to same Ag

  3. This specificity increases efficiency of immune responses and allows memory
• T cell receptor and Ab (B cell receptor) can recognise almost any protein or organic molecule
• Caveat


  T and B cells cannot distinguish friend from foe
• Activated correctly


  Very powerful weapon to fight pathogens
• Activated incorrectly


  Very dangerous, leads to autoimmunity and allergies
• Innate cells can recognise pathogens

  • Pattern-recognition receptors (PRRs)
  • Pathogen-associated molecular patterns (PAMPs)
  • Damage-associated molecular patterns (DAMPs)
• Innate Immunity


  • Not very specific, but can identify whether something is a pathogen
  • Fast response
  • No memory
• Adaptive Immunity


  • Very specific, but cannot tell what it is recognising
  • Slow response
  • Memory
• Innate immune cells decide

  • Friend from foe
  • Harmless from harmful
• T cell recognises


  Short 8-25 amino acid (peptide) sequences
• T cell can't recognise Ag on its own


  Ag has to be presented to it by a professional Antigen Presenting Cell (APC)
• Professional APC


  • Dendritic cells (DC)
  • Macrophages
  • B cells
• Naïve T & B cells


  Never seen Ag before
• Major Histocompatibility Complexes (MHC) I and II


  • Present Intra-cellular Ag
  • Present Extra-cellular Ag
• MHC


  • Ag (peptide sequence) lies in groove of MHC
  • MHC molecules can bind a range of different peptides
  • T cell Receptor binds both MHC and peptides
  • T cell can only recognise peptide when combined with MHC
• MHC class I


  Peptide sequences 7-11 aa long
• MHC class II


  Peptide sequences 13-25 aa long
• Major Histocompatibility Complex


  • Each MHC molecule can bind a range of different peptide sequences
  • Each of us express a diverse set of MHC molecules
  • MHC molecules need to be able to present a huge range of peptides
  • Different MHC alleles bind a different range of peptide sequences
  • The more MHC molecules you have, the more peptides you can present
  • Important for dealing with the breadth of different pathogens and preventing immune evasion
  • MHC genes are codominantly expressed meaning alleles inherited from both parents expressed equally
• MHC class I genes

  • HLA-A
  • HLA-B
  • HLA-C
• MHC class II genes

  • HLA-DP
  • HLA-DQ
  • HLA-DR
• MHC haplotype


  The set of MHC alleles present on each chromosome
• MHC genes are the most polymorphic genes in mammals
• There will always be someone in the population able to present any particular microbial Ag
• MHC molecules


  • The principle factor in defining acceptance or rejection of grafts
  • Foreign MHC molecules on graft activate the recipients T cells that then kill the graft
  • Need to match the MHC molecules (haplotypes) between host and donor as much as possible - Tissue typing
• We can smell MHC polymorphism
• Extra-cellular Ag


  • Presented by MHC class II
  • T helper (Th) cells
  • Regulatory T (Treg) cells
• Intra-cellular Ag


  • Presented by MHC class I
  • Cytotoxic T cells/lymphocytes (CTL)
• CD4


  • Only see Ag presented by MHC Class II
  • Express CD4 on surface
• CD8


  • Only see Ag presented by MHC Class I
  • Express CD8 on surface
• CD4 and CD8


  • Restrict T cell to MHC class II and MHC class I respectively
  • CD4 stabilises TCR interactions with MHC class 2
  • CD8 stabilises TCR interactions with MHC class 1
• MHC class II molecules

  • Present extra-cellular Ag
  • Only expressed by Professional APC
• Dendritic cells (DCs)


  • Immune sentinels, similar to macrophages
  • Express PRRs (like all innate cells)
  • Do not kill (unlike macrophages)
  • Scan for infection (via PRRs)
  • Sample environmental antigens
  • Take Ag to Lymph nodes to talk with T cells (macrophages stay at infection site)
• Three phases in the life of a Dendritic Cell

  1. Sampler: Takes up and spits out extra-cellular fluid and molecules

  2. Expresses PRRs to detect DAMPs and PAMPs

  3. Not very good at presenting Ag (this is good because mostly presenting self-antigens)

  4. DANGER: Takes in more environment molecules/Antigens

  5. Stops sampling the environment, carries antigens to the LN to present them to T cells
• • DC take Ag to LN
  • Naïve T cells circulate between LNs
  • Naïve T cells interrogate DC to see if presenting an Ag they recognise
• MHC class 2


  Used to present Ag to the T helper cell - controls specificity
• How does DC communicate Danger to tell the T cell


  'This Ag you are recognising comes from a pathogen'
• Dendritic cells (DCs)


  • Immune sentinels similar to macrophages
  • Express PRRs (like all innate cells)
  • Do not kill (unlike macrophages)
  • Their role: Scan for infection (via PRRs), Sample environmental antigens, Take Ag to Lymph nodes to talk with T cells (macrophages stay at infection site)