Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards
origin of NK and T cells?
Both arise from common lymphoid progenitor cell
Both part of the lymphocyte lineage
common lymphoid progenitor cell goes to innate lymphoid cells, B cells and T cells
why do we need cytotoxic lymphocytes?
as a means to destroy cells infected with bacteria, viruses or parasites and tumour cells
requires a cell-surface mechanism to display what is going on within a cell - MHC
There are “self” and ”non-self” – the immune system gets rid of “non-self”. But, what if the non-self was hidden inside the cells? The immune system needs to know what’s happening inside the cell by looking at the cell surface - this is what MHC class 1 is for.
MHC class 1 proteins?
these are found at the cell surface, form a structure that holds antigenic peptides for surveillance by T cells
display whats going on inside the cell
proteins expressed within a cell (whether healthy, mutated or resulting from infection) are processed and presented on MHC class I proteins - not just viral proteins
MHC class 1 are recognised by?
CD8+ cytotoxic T cells
MHC class I structure
Humans: HLA-A, -B, -C
Tissue distribution: on ALL nucleated cells
two polypeptides, non-covalently bound
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) - this protects against a wide range of pathogens and their tendency to mutate
High genetic variability within these genes
polymorphisms are in the upper peptide-binding part of the MHC protein - in and around the peptide binding groove
explain about the binding groove further
the amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”
substituting different amino acids produces different positive and negative charge between different MHC’s
size/shape of the pockets also vary
MEANS different peptides will bind to different MHC alleles, depending on the size/shape/charge of the pockets
the TCR recognises what and how does it bind?
two things:
MHC protein itself
Antigenic peptide presented by MHC protein
Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
- allows it to contact the MHC and the main part of the peptide, meaning the TCR can see both and differentiate accordingly
For cytotoxic T cells, the interaction between TCR and MCH isn’t paticularly strong - how is this fixed?
CD8, which acts as a co receptor and is needed for the T cell to make an effective response - strengthens MHC class I/TCR interaction
TCR binds to the α1α2 domains at the top
CD8 binds to the support domains (α3 and β2m) at the bottom, structural support region. This region is highly conserved - why? Being highly conserved means CD8 always binds there - too many variations would risk losing CD8 binding. The polymorphisms are all concentrated at the top around the peptide and TCR.
The same occurs with MHC class II and CD4.
Some microbes get rid of their peptides being presented on MHC class 1 to prevent cytotoxic T cell destruction - gives four examples?
- inhibition of MHC class I expression - adenovirus
- HSV blocks the TAP transporter, that transporter that gets the peptides from the cytoplasm to the ER
- HCMV has lots of different evasion mechanisms, one is retaining MHC in the ER, or shuttling MHC out of the ER so it can be destroyed
- HIV downregulates MHC class I from the cell surface
BACKUP and solution to this evasion is NK cells
What are NK cells?
Classical NK cells are large granular lymphocytes that are not T or B cells
Do not express T Cell Receptor (CD3) or B cell receptor
They express the cell surface marker CD56
They have cytotoxic functions and cytokine secretion (some are more cytokine specific)
Low NK cell activity correlates with what?
severe disseminating herpes virus infections
how is MHC class I recognised by NK cells?
innate immune receptors:
- Killer Ig-like receptors (KIR) - regulate NK cell activity
- Leukocyte Ig-like receptors (LILR) - regulate NK cell function
KIR and LILR are encoded in a gene complex on ch 19, called the leukocyte receptor complex/LRC
Function of Killer Ig-like receptors (KIR)
predominantly inhibitory, ‘don’t kill’ signal
KIR recognise MHC-I by binding to the same face as the TCR, and inhibit NK cells from releasing lytic granules
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”
KIR are polymorphic and recognise subsets of MHC-I alleles - Different KIR see different groups of MCH alleles
Individual KIR genes vary in their presence between individuals
Natural cytotoxicity receptors (NCRs)
Find them on NK cells, they provide an activating signal to NK cells
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
