Lecture 6: Innate Responses to Infection: Natural Killer Cells Flashcards
What are NK cells?
part of the ILC (innate lymphoid cells) family of cells
What does the development of NK cells require?
Id2, Nfil3 and eomesodermin (eomes)
presence of IL-15
How are NK cells distinguished?
lack Ag-specific receptors (i.e. TCR, slg)
not many receptors are uniquely expressed by NK cells
most commonly used combination is CD56+ CD3-
How do NK cells kill?
lyse target cells by releasing cytotoxic granules
-> perforin/granzyme dependent
What is TRAIL?
TNF related apoptosis inducing ligand -> interacts with DR4 and DR5 (death receptors)
What does engagement of DR4/DR5 lead to?
activation of caspase 8 and apoptosis
What are the key roles of NK cells?
immunity to viral infections and tumours
emerging role in reproduction
What do NK cells secrete?
cytokines e.g. IFNy, TNFa
chemokines e.g. XCL1
What turns on a NK cell?
cytokines -> type I interferons, IL-12, IL-15, IL-18 cellular interactions -> antibody dependent cellular cytotoxicity (CD18) natural cytotoxicity -> role of MHC class I and MHC-class I-like proteins
What is NK cell activity controlled by?
a balance of stimulatory and inhibitory signals
Which molecules activate NK cells?
FcR, NKG2D
activating siblings: KIR, NKG2C, Ly49, LILR
Which molecules inhibit NK cells?
inhibitory siblings: KIR, NKG2A, Ly49, LILR
What does antibody dependent cellular cytotoxicity require?
requires antibody (i.e. adaptive immune response) and CD16 (FcyRII)
What is CD16 (FcyRIII) associated with?
a “CD3”-like adaptor that contains ITAMS
Why don’t NK cells kill “normal” cells?
because “normal” cells express class I
Which receptors bind MHC class I?
inhibitory receptors -> prevents activation of NK cells
What are examples of susceptibility to NK cell lysis?
virus infection e.g. HSV, CMV can downregulate MHC class I expression tumour cells frequently have defective class I expression
What are Ly49 receptors expressed by and what are they members of?
expressed by rodent NK cells members of the C-type lectin superfamily recognise H-2K and H-2D class I molecules
What are CD94/NKG2A receptors expressed by and what are they members of? What do they recognise?
expressed by both rodent and primate NK cells members of the C-type lectin superfamily recognises non classical MHC class I molecules
What do CD94/NKG2A receptors recognise in humans and mice?
HLA-E (humans)
Qa-1^b (mice)
ubiquitous expression, not polymorphic
What is significant about HLA-E/Qa-1?
have peptide binding clefts specialised for presenting conserved peptides present in the signal sequence of other MHC class I proteins
What happens if a virus or tumour disrupts the expression of HLA-A, HLA-B or HLA-C?
there is a decrease in the amount of peptide entering the cell and interacting with HLA-E which results in a drop in HLA-E levels at the cell surface and a decrease in inhibitory signalling on the NK cell through CD94-NKG2A
What are killer cell immunoglobulin-like receptors (KIR) expressed by and what are they members of?
expressed by primate NK cells
members of the Ig-superfamily
recognise groups of HLA-A, -B and -C allotypes (HLA-C > HLA-B > HLA-A)
Which four epitopes present on groups of class I molecules does KIR recognise?
C1 (or group 1 HLA-C)
C2 (or group 2 HLA-C)
Bw4
A3/A11
Why could the four epitopes recognised by KIR present on groups of class I molecules be a requisite for survival of the population?
despite significant differences in HLA alleles present in distinct ethnic groups, all populations studied to date possess alleles from each group
How does KIR bind to HLA?
uses interdomain "elbow" regions to bind to HLA KIR binds over the C-terminal region of the peptide and the alpha 1 and 2-helices of the HLA class I
What impacts recognition by KIR?
the sequence of the peptide bound to the HLA class I protein
What is the role of unlicensed cells?
respond during acute viral infection
role for pro-inflammatory cytokines
What happens if HLA is not present on the cell (due to downregulation)?
NK cells are activated because there is no inhibitory signal
What is NKG2D?
activating receptor which is expressed by all NK and certain T cell subsets
What are characteristics of NKG2D ligands?
MHC class I-like molecules do not bind peptides do not associate with B2 microglobulin
What are examples of NKG2D ligands?
human -> MIC-A/B and ULBP (UL16 binding proteins)
mice -> RAE-1 (retinoic acid early inducible transcripts) and H60
How are NKG2D ligands regulated?
non constitutive -> low or absent in most adult tissues
inducible -> heat shock, viral infection, bacterial infection
frequently expressed on tumours/transformed cells
What does expression of NKG2D ligands indicate?
cellular stress -> infected/transformed cells
What is NKG2D ligand expression initiated by?
protein kinases ATM or ATR
induced as a result of DNA damage e.g. cleaved dsDNA or stalled replication forks
