6 T cells and receptors Flashcards
what is MHC in humans
HLA
what leads to killing of target cell
If they have the same TCR for target cell, need to recognise MHC and virus = killing
when is there no killing of target cell
If have a different peptide to one recognised by the t cell receptor = no killing
Germline organisation of the human T-cell receptor alpha and beta loci
- Variable region for the alpha and the beta
- Gene Rearrangement occurs by the same mechanisms that are used by B cells
After antigen stimulation of TCR what occurs
> no further mutation,
> no switching of constant regions
Gene rearrangement
- essentially same as first stage of Ig generation of diversity
- α and β chains on different chromosomes, 1 constant α genes and 2 constant β genes- no functional difference
- Recombination occurs putting a variable region, J region and C region for α –chain whereas β chain also has a D region
where does V region assembly occur
B and T cells
where does junctional diversity occur
B and T cells
where does transcriptional activation occur
B and T cells
where does switch recombination occur
B cells
where does somatic hypermutation occur
B cells
where does IgM, IgD expression on surface occur
B cells
what is the V region assembly process
somatic recombination of DNA
what is the junctional diversity process
imprecise joining, N-sequence insertion of DNA
what is the transcriptional activation process
activation of promoter by proximity to the enhancer
what is the switch recombination process
somatic recombination of DNA
what is the somatic hypermutation process
DNA point mutation
what is the IgM, IgD expression on surface process
differential RNA splicing
T cell receptor expression
Expression of the TCR on the cell surface requires association with additional proteins
T cell receptor named
Collectively termed CD3
when does the T cell receptor signal occur
when T cell receptor recognises the antigen
how does a helper T cell work
Helper T cell work with antigen presenting cell, shows it the antigen via CD4 T cell (MHC 2)
how does a cytotoxic T cell work
Cytotoxic T cell work with target cell, presenting the MHC to the CD8 on cytotoxic T cell = death (MHC 1)
what MHC does helper T cell work with
MHC2
what MHC does cytotoxic T cell work with
MHC1
T cell activation and differentiation process
- Naive T cells circulate in blood but enter secondary lymphoid organs e.g. lymph nodes
- Enter through afferent lymphatics
- Mingle with antigen presenting cells (APCs) if don’t encounter antigen leave through efferent lymphatics
- If meet antigen proliferate and differentiate into effector cells
T cell/antigen recognition
- If correct peptide seen by TCR conformational changes in cell are induced by TCR being ligated
- Interaction with APC stabilised and cell proliferates and it and its progeny become effector cells
- Need other triggers from APC….co-stimulation
examples of professional APCs
Macrophages, Dendritic cells and B cells have B7 or otherwise known as CD80/86 co-stimulatory molecules
any cell with MHC2
what do professional APCs do
binds to CD28 on surface of T-cell and a second signal is needed differentiation
what do you need for differentiation and proliferation
TCR/CD4/CD8 signals and co-stimulation
Interactions between APCs and T cells
CD4/CD8 ensuring it stays together
Various ligands involved in adhesion, that stick the two cells together
Soluble signals between cells using cytokines
what signals do APCs deliver to naïve T cells
activation
survival
differentiation
when does an activation signal in APC occur
MHC peptides and T cell receptor interaction
when does a survival signal in APC occur
B7 and CD28 interaction
what happens if there is no survival signal
they stop proliferating - to keep going
when does a differentiation signal occur
what type of antibody become
when are T cells activated
Once all receptors ligated the T cell is activated
what does T cell activation induce
- Express receptors for IL-2
2. Produce IL-2 (Autocrine system)
what leads to proliferation
IL-2 binding to IL-2R
when does T cell proliferation occur
Naïve T cells express low affinity IL-2 receptor
Activated T cells express the high affinity IL-2 receptor (IL-2Ralpha, beta and gamma chains) and secrete IL-2
Binding of IL-2 to high affinity receptor sends a signal to the T cell
signal from IL-2 receptor induces T-cell proliferation
effect of IL-2 receptor activation
high alpha chain numbers per cell
Differentiation - what T cell is made
- Mature naive T cells are already committed to being helper or cytotoxic T cell
- Cytotoxic cells once activated are effector cells (killing cells)
- Helper T cells have a more complex differentiation pathway once stimulated by antigen
- This is affected by signals from APC
What type of helper cell made
type of helper cell it becomes is not fixed
Different cytokines will make you a different T helper cell
what characterises TH1
characterised by making IL-2 and gamma interferon
what does TH2 make, and what must be present
TH2 cells in the presence of IL-4 make IL-4 and IL-5
examples of regulatory cells
IL-10, TL1 and TH3 are a different type of regulatory cells
Treg cells effect
dampen immune response – regulate
types of effector T cells
CD8 cytotoxic T cells CD4 TH1 cells CD4 Th2 cells CD4 TH17 cells CD4 regulatory T cells
CD8 cytotoxic T cell function
kill virus-infected cells
CD4 TH1 cell functions
activate infected macrophages
provide help to B cells for antibody production
CD4 TH2 cell functions
provide help to B cells for antibody production, especially switching to IgE
CD4 TH17 cell functions
enhance neutrophil response
CD4 regulatory T cell function
suppress T cell responses
what pathogens does CD8 target
viruses
some intracellular bacteria
what pathogens does CD4 TH1 target
microbes that persist in macrophage vesicles
extracellular bacteria
what pathogens does CD4 TH2 target
helminths
parasites
what pathogens does CD4 TH17 target
extracellular bacteria
what does the cytotoxic T cell recognise
MHC Class I peptide complex in secondary lymphoid tissues
what happens when cytotoxic cells
- migrate to tissues and site of infection
- effector cells package cytotoxins into modified lysosomes
- On seeing infected cell release this cargo very selectively on infected cells
cytotoxic cells and infection
- migrate to tissues and site of infection
- effector cells package cytotoxins into modified lysosomes
- On seeing infected cell release this cargo very selectively on infected cells
process of infection when cytotoxic cell recognises infection
CTL recognises and binds virus-infected cell
CTL programs target for death, including DNA fragmentation
CTL migrates to new target
Target cell dies by apoptosis
Dumps cytotoxic on cell-Specifically kill cell with its own peptide on it
T cell and killing of infected cells
Infecting cell that is programmed for cell death, those without its own peptide are not infected – specific
Programmed for cell death
Neighbouring uninfected cells are therefore not killed
Two mechanisms of killing: Both lead to apoptosis of the target cell
Granule exocytosis pathway
FAS pathway
what is the Granule exocytosis pathway
perforin make holes in the membrane
Perforin/Granzyme Killing process
Granules are released from the CTL onto the target cells
Secretion of electron dense granules
Perforin
in vitro can lyse cells - poreformin - but major role is probably to target granzyme to the right place
when is there capase activity
If a cell has shut down caspase activity - (viruses will do this)
where does granzyme act
Granzyme can act down stream of caspase - also cleaving at ASP
FAS mediated Killing process
FAS receptor - member of the TNF family of death receptors
Engagement of the Fas receptor leads to aggregation of intracellular death domains
Recruits procaspase 8
What happens when helper T cell meets antigen
Can differentiate down a number of pathways
what does differentiation pathways depend on
depends on a number of factors
- cytokines produced by innate IR
- cytokines produced by the APC
- bystander cytokines- eg Th1 and Th2 cells cross regulated therefore bias can occur
what is central to killing of intracellular bacteria
TH1 cells
Help for Ab production
- Th2 cells help B cells to make antibody
- Only activate B cells that recognize the same antigen
- In secondary lymphoid tissues mature B cells present “their” antigen and pass through T cell zones
- When antigen in B cell MHC recognised by Th2 TCR the B cell becomes trapped and activated
Differentiation
triggered by cytokines it exposued to (happens in secondary lymphoid tissue) to which IL made
B cell presentation
B-cell presents antigen in MHC it is notable that the peptide in the MHC
May be a totally different epitope to that recognised by the antigen
Helper TH2 cell delivers the second signal via CD40 ligand and cytokines
B cell proliferates and differentiates into plasma cells
