Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
Innate and adaptive immunity - define both
Innate: non-specific (or broadly specific), immediate response
Adaptive: highly-specific, delayed response
Origin of NK and T cells - compare
Both arise from common lymphoid progenitor cell
Both part of the lymphocyte lineage
Role of cytotoxic lymphocytes + what do they require
We need cytotoxic cells as a means to destroy
cells infected with bacteria, viruses or parasites
Tumour cells
This requires a cell-surface mechanism to display what is going on within a cell
MHC class I - found where, function and recognised by what
MHC class I proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells
MHC-I = recognised by CD8+ cytotoxic T cells
Intracellular proteins are presented at
Intracellular proteins are presented at the cell surface by MHC class I
MHC class I structure in humans and the distribution
Humans: HLA-A, -B, -C
Tissue distribution: all nucleated cells
two polypeptides, non-covalently bound:
MHC class I structure - alpha vs beta2 microglobulin
Alpha chain = 45 kd
Polymorphic
Glycosylated
Inserted in membrane
B = 12kd
and opp. for rest
MHC class I proteins are central to anti-viral immune responses, so why don’t we see many pathogens that have mutated to avoid antigen presentation?
Multiple genes (e.g. two copies each of HLA-A, B and C)
High genetic variability within these genes
Amino acids in the MHC peptide binding groove create
Amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”
MHC-I and MHC-II play a central role in the
MHC-I and MHC-II play a central role in the ability of the immune system to distinguish self from non-self
TCR recognise what two things
TCR recognise two things
MHC protein itself (hence compatibility…)
Antigenic peptide presented by MHC protein
T cell receptor recognition of MHC - describe
TCR recognises both the MHC protein and the peptide antigen being presented by it
Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
Compare binding sites for CD8 and TCR
CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response
TCR binds to the α1α2 domains
CD8 binds to the support domains (α3 and β2m)
Similar situation for CD4 and MHC-II
List and describe effects of microbes on MHC/TAP
Microbes may subvert MHC upregulation
Inhibit MHC-I transcription (adenovirus)
Block TAP activity (HSV)
Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
Target MHC-I for disposal from ER (HCMV)
Downregulate MHC-I from cell surface (HIV)
What are NK cells?
Classical NK cells are large granular lymphocytes that are not T or B cells
NK cell receptor expression
Do not express T Cell Receptor (CD3) or B cell receptor
Do express the cell surface marker CD56
CD3-CD56+
NK cells function
Cytotoxic functions and cytokine secretion
Low NK cell activity correlates with
Low NK cell activity correlates with severe disseminating herpesvirus infections
Killer Ig-like receptors (KIR) - function
Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer cells
Leukocyte Ig-like receptors (LILR) - function
Leukocyte Ig-like receptors (LILR) are innate immune receptors that regulate the functions of NK cells
KIR and LILR are encoded in a
KIR and LILR are encoded in a gene complex (the leukocyte receptor complex or LRC) on chromosome 19
Function of Killer Ig-like receptors (KIR)
When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules
Explain the concept of “missing self” in relation to KIR’s
Some viruses down-regulate MHC-I as a means to evade cytotoxic T cells, loss of MHC-I is also a common feature of tumour cells
If a target cell does not express MHC-I then there is no KIR inhibition, lytic granules will be released to lyse the target
Known as “missing self”
Killer Ig-like Receptors (KIR) - which face do they bind to and do what
Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
recognise subsets of MHC-I alleles
Killer Ig-like Receptors (KIR) - explain disease associations of KIR’s
KIR are also polymorphic, as well as being polymorphic individual KIR genes vary in their presence between individuals
Different MHC-I/KIR combinations show disease associations e.g. in HIV infection
Killer Ig-like Receptors (KIR) - list allele specificity
HLA-class I specificity
KIR2DL1 - list allele specificity
Group 2 HLA-C alleles expressing Lys80 (such as, HLA-Cw2, -Cw4, -Cw5, -Cw6)
KIR2DL2/3 - list allele specificity
Group 1 HLA-C alleles expressing Asn80 (such as HLA-Cw1, -Cw3, -Cw7, -Cw8)
KIR3DL1 - list allele specificity
HLA-Bw4 alleles (e.g. HLA-B27)
Natural cytotoxicity receptors (NCRs) - function
These provide activating signals to NK cells, but are not well characterised
Natural cytotoxicity receptors (NCRs) - compare action of all the types
NCR 1 binds viral hemagglutinin
NCR2 – binds a ligand that is expressed on tumor cells and upregulated by viral infection
Ligand for NCR3 is a stress induced
protein
Target cell death or survival depends on
Target cell death or survival depends on balance of activating and inhibitory signals
Antibody-dependent cell-mediated cytotoxicity (ADCC) - describe
AB binds AT on target cell surface
Fc receptors on NKC recognize AB
NK signalled to kill target due to FcR cross-linking
=
target cell dies by apoptosis
Why do NK cells kill tumour cells?
Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I.
This makes them more susceptible to NK cells.
Mechanisms of lysis – cytotoxic granules
NK cells and T cells carry granules filled with cytotoxic proteins
Release cytotoxic granules at site of contact with target cell
(must be directed in order to avoid damaging innocent bystander cells)
CD8 cells can trigger apoptosis of target through Fas/FasL interaction - describe
This process does not depend on cytotoxic granules
Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
Loss of Fas can result in
Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)
NK cell - describe the:
Receptor type
Ligand type
Effect of MHC I absence
Effect of MHC I presence
Receptor type = NKR (activating and inhibitory)
Ligand type = MHC I, MICA/B, immune complexes etc
Effect of MHC I absence = immediate cytotoxicity (‘missing self’)
Effect of MHC I presence = inhibitory signal to NK cell
Cytotoxic T cell - describe the:
Receptor type
Ligand type
Effect of MHC I absence
Effect of MHC I presence
Cytotoxic T cell - describe the:
Receptor type = T cell receptor
Ligand type = peptide-MHC I complex
Effect of MHC I absence = lack of recognition
Effect of MHC I presence = TCR engagement
CTL cells in terms of:
CD8 use Receptor expression Response to MHC class I Engaging with target Memory
Cytotoxic T cells
CD8 use = Use CD8 as a co-receptor for MHC class I
Receptor expression = Each express a unique receptor with high specificity for a single MHC/peptide complex
Response to MHC class I = Survey MHC class I on the surface of other cells, searching for foreign antigens
Engaging with target = Initial activation of naïve T cells, followed differentiation and proliferation required
Memory = yes
NK cells in terms of:
CD8 use Receptor expression Response to MHC class I Engaging with target Memory
CD8 use = Do not use a co-receptor for MHC class I, do not express CD8
Receptor expression = Invariant receptors with broader specificity for MHC allele subsets
Response to MHC class I = Respond to the absence of MHC class I
Engaging with target = Ready to act on encountering targets in the periphery
Memory = No memory
