Lecture 16 - Lymphocyte Subsets - CD4+ T cells Flashcards
What are the functions of ‘helper’ T cells?
Indirect elimination of pathogens
Through assistance to other cells w/ cytokine release
Help for:
• B cells
• CTLs (though DCs)
• Macrophages
Describe the restriction of helper T cells
MHC class II restricted
How are Th cells activated?
Dendritic cell presentation of antigen in the context of MHC class II
Can CD4+ T cells be converted into a CD8+ T cell?
No
But CD4+ can differentiate into different lineages
What determines commitment of CD4+ T cells?
- TCR interaction w/ MHC II (Signal I)
* APC cytokine release (Signal III)
Describe T cell help for macrophages
- Infected macrophages are expressing:
• MHC II + antigen
• CD40
• IFN-γ receptor - Th1 cells recognise the foreign antigen in the context of MHC class II w/ TCR
- Th1 releases IFN-γ which binds to IFN-γ receptor on macrophage
- IFN-γ assists in eliminating intracellular pathogens:
• increased ROS etc.
Which pathogens cause intracellular infections of macrophages?
Mycobacteria → Tuberculosis
Salmonella → Typhoid fever
What is the definition of AIDS?
CD4+ T cell blood concentration less than 200 per mL
Describe T cell help for CTLs
Helper T cells help the DCs to help the CTLs
(ménage à trois)
- Upregulation of CD40L on the CD4+ T cell
- (Newly acquired) CD40L on CD4+ T cell stimulates CD40 on DC
- DC up-regulation of co-stimulatory molecules, such that it’s able to provide the signals to CD8+ T cells
- B cell production of IL-2 also stimulated by DCs, released onto IL-2R on T cell
Describe the role of IL-2 in activation of CD8+ T cells
CD8+ T cells release IL-2 onto themselves
(Autocrine signalling)
This is the signal for proliferation of T cells
Which type of ‘helper’ T cells assist B cells?
Describe this ‘help’
Tfh cell (follicular helper cell)
- TFH upregulate CXCR5 and B cells upregulate CCR7 → they meet in the middle at the MZ
- Cognate interactions between an antigen-specific TFH and activated B cells
- CD40L ligates CD40 on the B cell
- Upregulation of ICOSL and IL-21R on B cell
- ICOSL interacts with ICOS on the TFH resulting in IL-21 production
- IL-21 binds to IL-21R on the B cell, upregulating Bcl6
- Bcl-6 is s transcription factor needed to ensure survival of the activated B cells ensuring continued germinal centre reactions
Where is CXCL13 primarily expressed?
In the follicle
What is the ligand for CCR7?
Where are these expressed?
CCL19 & CCL21
In the paracortex
How do we get Th cells to move to the periphery of the follicle?
Upregulation of:
• CXCR5
as well as previous expression of
• CCR7
Follows two chemokine gradients, towards:
• Follicle
• Paracortex
So it is stuck in the middle, which is the boundary between the paracortex and the follicle
Describe the outcome if identical CD4+ T cells are stimulated with: • IL-4 • IL-12 • IL-6 • IL-6 + TGF-β • TGF-β
IL-4 • differentiates into Th2 • Th2 makes IL-4 • Extracellular, anti-parasite immunity • 'Helps' B cells make IgE
IL-12
• differentiates into Th1
• Th1 makes IFN-γ
• Intracellular, viral infections
IL-6
• Differentiates into Tfh cells
• Tfh cells express IL-21 and ICOS
• help B cells at the boundary of the follicle
IL-6 + TGF-β • Differentiates into Th17 • Th17 makes IL-17 • Pro-inflammatory • Extracellular bacterial infection
TGF-β
• Differentiates into Treg cells
• Treg makes IL-10 and TGF-β
What is the role of IL-2 in Th cells?
Autocrine signalling
Required as a growth hormone for proliferation
Is it possible for a Th2 to revert to a Th1?
Yes
Through signalling with IL-12
However, they are committed to being CD4+ cell (can’t become CD8+ T cells)
What is the structure of IL-12?
It is a heterodimer:
• IL-12p40
• IL-12p35
What is the structure of IL-23?
Heterodimer:
• IL-12p40
• IL-12p19
What stimulates Th17?
What does Th17 produce?
Stimulated by IL-6 (also IL-23)
Produces:
• IL-17
• IL-6
• IL-22
What is the role of IL-17?
Strong pro-inflammatory cytokine
Important in the activation of neutrophils
Which pathogens are neutrophils good at clearing?
Extracellular Bacteria
• S. aureus
• S. pneumoniae
Which Th cell subset are good at stimulating neutrophils?
Th17
Which Th cell subset is the likely culprit in many autoimmune diseases?
Th2
Th17
Which costimulatory molecules are important in T cell help for B cells?
On T cell:
• CD40L
• ICOS
On B cell:
• CD40
• ICOSL
Which important molecules do Tregs express?
FOXP3
CD25 (aka α chain of the IL-2R)
Describe the induction of Tregs
Stimulated by TGF-β release from DC
Which cytokines do Tregs release?
IL-10
TGF-β
Describe the function of Tregs
Suppression of:
• Th1
• Th2
• CD8+ T cells
Through the release of suppressive cytokines:
• IL-10
• TGF-β
What is a Treg deficiency?
IPEX
• X-linked defect in FOXP3
Which transcription factor is important for: • Tfh cells • Th17 • Th1 • Th2 • Treg
Tfh: Bcl-6 Th17: RORγT Th1: T-bet Th2: GATA3 Treg: FOXP3
What happens without CD4+ T cells?
Acquired immunodeficiency syndrome
What type of cell are NK T cells?
Lymphocytes
Some people describe them as T cells w/o the TCR
However, they then found some that had TCRs
They aren’t T cells though, because they use a very small repertoire of α and β chains
→ ‘Invariant’
Restricted to CD1d
What sort of antigen do NK T cells recognise?
How do they recognise their antigen?
Lipid and glycolipid antigen
Presented in the context of CD1d
Describe the TCR of NK T cells
‘Invariant’
Express a very small repertoire of α and β chains
Which cytokines do NK T cells produce?
What is their function?
IL-4
IFN-γ
Function:
• Immune regulation
• Autoimmunity
• Anti-microbial immunity
What is CD1d?
Molecule on APCs that loads lipid and glycolipid antigen for recognition by NK T cells
What are the major biological differences between NK T cells and other T cells?
- Recognise lipid and glycolipid antigens in the context of CD1d
- Have ‘invariant’ TCRs
Which pathogens may NK T cells be particularly good at launching a response against?
Mycobacteria
These have a lipid, acid fast capsule
Not confirmed
What are γ/δ T cells?
Where are they located?
What do they respond to?
Have γ/δ TCR instead of α/β
• Semi-invariant TCR
Located in the skin
No-one knows what they respond to, as yet
What are innate lymphoid cells?
TCR?
What are they important for?
A newly discovered range of lymphocytes
Lack a TCR
Important for barrier immunity
Describe the effector function of innate lymphoid cells
Quite similar to normal Th cells:
• respond to cytokines to produce the various phenotypes
Do all ‘helper’ T cells help B cells?
No
It is only Tfh that help B cells in the marginal zone of the LN.
Their help stimulates them to undergo SHM and CSR
Which cytokines do Tfh release onto B cells?
IL-21
Compare cytokine release from the following cells: • Th1 • Th17 • Tfh • Th2 • Treg
Th1:
• IFN-γ
• IL-2
Th2:
• IL-4
• IL-5
• IL-13
Th17:
• IL-17
• IL-6
• IL-22
Treg:
• IL-10
• TBG-β
Tfh:
• IL-21
Compare the classical function of the following cells: • Th1 • Th17 • Tfh • Th2 • Treg
Th1:
• Macrophage activation IFN-γ
• Intracellular pathogen killing
Th2: • IgE responses from B cells IL-4 • Parasite immunity • Allergy • Barrier function IL-13 • Eosinophil activation IL-5 • M2 macrophage activation
Th17:
• Neutrophil responses, IL-17
• Pro-inflammatory, IL-17
• Barrier function, IL-22
Treg:
• Immune suppression, IL-10, TGF-β
Tfh:
• B cell help, IL-21
Compare the cytokines which stimulate differentiation into the following cells: • Th1 • Th17 • Tfh • Th2 • Treg
Th1:
• IL-12
• IFN-γ
Th2:
• IL-4
Th17:
• IL-6
• TGF-β
Treg:
• TGF-β
Tfh:
• IL-6
With which surface expressed molecules do Tfh stimulate B cells?
CD40L
IL-21, released
From what do NK T cells develop?
Double negative thymocytes
i.e. they express neither CD4 or CD8
