NK cells, innate lymphoid cells, innate-like lymphoid cells

• What is the main function of innate and innate-like lymphocyte populations?

  These rare populations provide a source of cytokine to keep infection under control in early stages. This is required to keep the host alive during early stages of infection while the adaptive lymphocyte responses are generated.
• What are innate lymphoid cells?

  This is a discrete population of lymphoid cells that play a key role in the first line of defence against microbes. These cells exist in the same states as the adaptive immune cells since they share transcription factors, which stimulate the expression of specific cytokines.

  • ILC1 same state as T-helper 1, with T-bet expression
  • ILC2: same state as T-helper 2, with GATA-3 expression
  • ILC3: same state as T-helper 17 and 22, with ROR-gamma-t expression
  • NK cells: same state as CD8+ T cells, with Eomes expression
• Describe which cytokines induce differentiation of specific ILCs

  • ILC1 and NK cell: IL-12, IL-15, and IL-18
  • ILC2: IL-25, IL-33, and TSLP (inhibits ILC3 differentiation)
  • ILC3: IL-1beta and IL-23
• Where are ILCs found in the body?

  ILCs are found from birth in many tissues, predominantly barrier tissues, e.g:

  • Lungs: ILC2 located close to blood vessels in the lungs to recruit eosinophils from the blood
  • GI tract: LTi cells in Peyer’s patches and lymphoid follicles interact with B cells to promote IgA production, which helps coexist with local microbiota to prevent dysbiosis.
• Describe the members of the ILC family and their functions

  NK cell: macrophage activation, production of oxygen radicals and cytotoxicity.

  ILC1: Deals with intracellular virus and bacteria via macrophage activation and oxygen radical production

  ILC2: deals with Helminths via mucus production, alternative macrophage activation, extracellular matrix and tissue repair, vasodilation, and thermoregulation

  ILC3: deals with extracellular bacteria and fungi via phagocytosis, anti-microbial peptides, and epithelium survival
• Describe the effector cytokines of ILCs


  NK cell: granzymes, performing, and IFN-gamma

  ILC1: IFN-gamma and TNF-alpha during early stages of infection

  ILC2: IL-4, IL-5, IL-13, and Areg

  ILC3: IL-17, IL-22, and GM-CSF
• Describe the general action of ILCs


  1. Produce cytokines to induce immunity and inflammation
  2. Induce an inflammatory cascade via interactions with other immune cells
  3. Highly enriched in barrier tissues and act on epithelial cells to reinforce the epithelial barrier to prevent microbes from accessing to blood stream and induce mucus production
  4. Specialised roles in immunity to a broad range of pathogens
• How are ILCs dependent upon common gamma-chain cytokines?


  ILCs are dependent upon common gamma chain cytokines including IL-2 and IL-7 (all ILCs) and IL-15 (NK cells) for their development, survival and proliferation in tissues. ILCs express receptors that sense cytokine cues, which act as growth factors for ILCs.
• How are ILCs activated?


  ILCs lack antigen specific receptors and do not undergo somatic combination, instead they act as pre-primed effector cells that are constitutively present in the tissue and respond rapidly. ILCs become activated and produce cytokine in response to tissue signals following damage or infection, either:

  • directly by signals released by damaged cells: e.g., intestinal epithelial cells
  • indirectly by cytokines released by myeloid cells, e.g., DCs, that sense microbial patterns, i.e., TLR ligands
• Describe direct activation of ILC2


  Damage to barrier to surfaces, e.g., Helminth infection, causes release of danger associated cytokines from barrier epithelium (IL-25, IL-33, TSLP). ILC2 respond by producing IL-4, IL-5, and IL-13, which drive mucin production and muscle contractility to clear worm infections but also promote type-2 inflammatory diseases, such as asthma. These cytokines are known as alarmins, which alarm the immune system of danger.
• Describe the action of ILC3s


  Produce effector cytokines:

  • IL-17A: attracts neutrophils
  • IL-22: acts on epithelial cells to induce secretion of Antimicrobial peptides and reinforce barrier function

  Important in immune response against extracellular bacterial and fungal pathogens and critical for maintaining a healthy balance of commensal bacteria.
• Describe Lymphoid-tissue inducers


  ILC3 contain two subsets that express ROR-gamma-t and produce IL022 but differ in expression of surface phenotype markers. One subset is know as lymphoid tissue inducer cells, which are critical for development of lymph nodes and secondary lymphoid structures, e.g., Peyer’s patch, in the foetus. They also support formation of intestinal lymphoid structures in adults known as cryptopatches and isolated lymphoid follicles.
• How do NK cells monitor ’altered self’ cells?


  NK cell response is determined by a balance of inhibitory and activating signals. These cels surveil MHC-I expression to prevent killing of healthy self cells. Cancer interferes with cellular machinery to prevent MHC-I expression and tips the balance of activatory and inhibitory receptors towards NK cell activation. Lack on inhibitory signals can also result in NK cell activation and killing of target cell.
• Describe activating and inhibitory NK activation signals

  Inhibitory: MHC-I on target cell and inhibitory receptor on NK cell

  Activating: CD94 or NKG2A on the NK cell with region of MHC-I on target cell
• Describe the NK receptors


  Encoded within two gene clusters:

  • Killer lectin-like receptors: human chromosome 12
  • Killer immunoglobulin-like receptors: human chromosome 19

  Individual NK cells express only a selection of the available receptors, but the selection varies from cell to cell. NK cells express diverse combination of receptors within a signal individual.
• Describe inhibitory NK activation signals

  MHC-I on target cell and inhibitory receptor on NK cell. Longer cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which, following ligand binding, are phosphorylated on their tyrosine residue and recruit phosphatases to interfere with and suppress activating signals
• Describe activating NK activation signals

  Activating: CD94 or NKG2A on the NK cell with region of MHC-1

  • Associate with accessory molecules such as DAP12 containing immunoreceptor tyrosine-based activatory motifs (ITAMs), which, upon ligand binding, become phosphorylated on their tyrosine residue and trigger signal transduction and NK cell activation
• How do NK cells detect damaged, infected or stressed cells?


  Ig-like receptors:

  • NKp30, NKp44, and NKp46

  Lectin-like receptor:

  • NKG2D: ligands are MHC-like molecules, MIC-A, MIC-B, or RAET1 family members, whose expression is induced by cellular stress. Recognition by NKG2D acts as a generalised danger signal to the immune system.
• What are innate-like lymphoid cells?

  Differ from ILCs as they express a restricted form of the T cell receptor and differ from adaptive immune cells since they:

  • have only limited and restricted repertoire of antigen recognition
  • Produce cytokine without need for clonal expansion and polarisation

  Major populations of innate-like lymphocytes, e.g., NKT cells
• What are invariant NKT cells?


  These come in different subsets and express an invariant alpha-beta TCR that recognises lipid antigens presented by the MHC-like molecule CD1d on APCs. Like other innate lymphocytes, they cannot be boosted or form memory response.
• Describe the function of invariant NKT cells


  INKT cells help protect against microbial infections via the production of cytokines and interacting with other cells. E.g., they can produce IFN-gamma to protect against viral infections. They can also regulate cytotoxic T lymphocytes to enhance antitumour immune responses.
• Describe the TCR dominated activation model of iNKT cells

  APCs present lipid antigen on CD1d molecule, which interacts with TCR on the iNKT cell to produce a strong TCR signal, accompanied by weak cytokine signal.
• Describe the cytokine dominated activation model for iNKT cells


  Presentation of lipid antigen on CD1d molecule, which interacts with TCR on the iNKT cell to produce a weak signal, accompanied with strong cytokine signal.
• What are gamma-delta T cells?


  These arise from the same progenitor as alpha-beta T cells in the thymus and are amongst the first T cells generated in embryos where they seed barrier tissues, e.g., skin, lungs. Multiple subsets develop prior to birth with restricted V-gamma chain usage. Certain types have restricted cytokine producing ability. They are considered innate as they have restricted TCR chain and respond rapidly without need for proliferation and polarisation.
• Describe the different types of antigen that can be recognised by gamma-delta T cells


  • Lipids presented on CD1 class molecules
  • Phosphoantigens including those produced by bacteria
  • Butyrophilin molecules that regulate gamma-delta T cells in tissues
  • MHC-like stress ligands (similar to NK cells)