Introduction Background

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Introduction

• Authors aim to show that natural killer (NK)
  cells are involved in adaptive immunity

• NK cells are lymphocytes important in innate
  immunity (intracellular pathogens and ADCC)

• NK cells have similar functions to T cytotoxic
  cells
• induce apoptosis in infected cells
• mediated by recognition of cognate cell surface
  antigens
• - secrete IFN-?

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Introduction

• Mice devoid of T and B cells can elicit
  hypersensitive responses to haptens that persist
  weeks after infection

• 4 phases to an adaptive immune response
• Expansion
• Contraction
• Memory
• Secondary/ Recall

• Last two phases have not been shown in NK cells
• Authors investigated whether NK cells are able
  to undergo all four phases in response to
  infection

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Experimental methods

• Used mouse cytomegalovirus (MCMV) model
• NK Ly49H receptor recognises m157 viral protein
  on surface of infected cells
• Extracted NK cells from wild type (B6) and
  DAP12-deficient mice

• Used lethally irradiated mice

• Cells were identified and quantified by flow
  cytometry (FACS)
• Used dye CFSE and stained with bromodeoxyuridine
  to assess cell proliferation

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Expansion and Contraction

• In wt, NK levels reach 'ceiling' - inhibits
  further proliferation
• Experiment
• Decrease initial precursor frequency of fully
  functioning wt Ly49H
• Reduced to 25 of total NK cell number
• Expanded and contracted in frequencies comparable
  to wt
• Reduced to 10 of total NK cell number
• Expanded and contracted in frequencies comparable
  to wt
• Greater proliferation than 25 reduction of cells

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Expansion and Contraction - Controls

• Transferred NK cells were labelled with
  fluorescent CFSE
• Confirmed that only Ly49H were dividing

• Control DAP12-deficient mice were infected with a
  mutant virus
• Confirmed that the Ly49H receptor was specific
  for the m157 antigen

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Memory

• Ly49H NK cells that could be distinguished from
  naive Ly49H NK cells by FACS analysis
• found in mice up to 70 days after infection
• could be isolated from lymphatic and
  non-lymphatic tissues
• Memory and naïve Ly49H NK cells were applied to
  immobilised antigens
• capable of de-granulating and producing IFN-?
• response heightened in comparison to naïve NK
  cells

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Recall Response

• Memory cells were tested to see if they are
  more protective than naïve NK cells
• Both cell types were transferred into newborn
  mice
• Greater survival rates associated with memory NK
  cells

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Conclusions

• NK cells display all four phases of adaptive
  immune response
• NK cells could be
• evolutionary precursors to T cells
• may have co-evolved with T cells

• As NK cells possess aspects of both branches of
  immunity, they may have to re-categorised
• This will have knock-on effects for vaccination
  development strategies

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Future Experiments

• Investigate NK cell resposes to other pathogens
• Can all four phases be seen in responses mediated
  by other NK receptors?
• Investigate the viability of vaccines containing
  NK cell ligands
• Use this experimental toolbox to study other
  cells of the innate immune system
• Do dendritic cells have similar memory and
  immune cell specificty functions?