T cell differentiation and function Flashcards
What happens after a T cell recognises its antigen?
- APC presenting a peptide via MHC to T cell which becomes activated
- Clonal expansion
- Differentiation
- Contraction of some cells to memory pool and some apoptosis
What is a naive T cell?
It is a T cell which undergone development in the thymus, passed positive and negative control, rearranged its alpha and beta chain of TCR and left to the periphery but have not encountered its antigen yet and did not undergo differentiation.
Where usually T cell activation, expansion and differentiation occur?
Secondary lymphoid organs.
Naive T cells express lymphoid homing receptors, which allows them to travel through lymph nodes and this is where DCs which took up an antigen will travel to present to T cells. After differentiation, T cells exit the lymph node and travel to the site of the infection.
Homing receptors
Different T helper subsets have different homing receptors that allow them to go to different sites of inflammation.
What are 2 different types of memory T cells?
- Central memory - they reside in lymph nodes
- Effector memory - they reside in tissues, further from lymph nodes
How T cells become exhausted?
By chronic antigen stimulation by virus or in cancer.
Lymph node homing receptors
- CD62L
- CCR7
They are highly expressed by naive T cells and central memory T cells to circulate through lymph nodes
What signals are needed for activating T cells?
- Signal 1: TCR and MHC
- Signal 2: CD80/86 and CD28
- Signal 3: Cytokines
Cytokines can influence the subset that the T cell will differentiate into
What types of T cells are there?
- CD8 cytotoxic T cells
- CD4 Th1 cells
- CD4 Th2 cells
- CD4 Th17 cells
- Tfh cells
- T regs
CD8 T cells
- function as cytolytic, killing cells
- produce a lot IFN-y
- recognise peptides through MHC I
- two major mechanisms for killing: 1) granules containing perforin and granzymes, they can make holes in the membrane
2) Fas ligand (FasL) on T cell binds to Fas on the target cell triggering apoptosis (death receptor signalling) - release cytokines e.g IFN-y, TNF-a, IL-17
- if exhausted, they have limited killing and cytokine production.
- are targets of immunotherapy
How the fate of which subset the T cell will differentiate into is predicted?
Innate immune cell, the one which is presenting the antigen will instruct T cell based on the cytokines it secretes.
Th1 cells
- They produce IFN-y
- Important for immune response to intracellular pathogens (e.g. Listeria or TB) and extracellular bacteria
- Activate infected macrophages
- Intracellular pathogens evolved to survive inside a macrophage after being engulfed and Th1 cells produce IFN-y which signals in macrophages to produce reactive oxygen species which augment the killing capacity of macrophage.
- Differentiation into Th1 is directed by IL-12
Th1 differentiation
- IL-12 when bound to IL-12 receptor on T cell induces STAT4 signalling
- This upregulates the expression of transcription factor T-bet
- T-bet is a master transcription factor for Th1 cells
- T-bet binds IFN-y and promotes IFN-y expression and it binds IL-12 beta 2 gene so it increases expression of IL-12 receptor
- IFN-y signalling also upregulates IL-12 receptor beta 2
- T-bet antagonises other transcription factors like GATA3
- T-bet binds to IL-4 gene and shuts down its expression
Th2 differentiation
- IL-4 when bound to IL-4 receptor on T cell induces STAT6 signalling
- This upregulates expression of transcription factor GATA3
- GATA3 upregulates expression of IL-4 and IL-4 receptor
- GATA3 antagonises T-bet
- GATA3 binds to INF-y and shuts down its expression
Th1 activating infected macrophage
- Bacteria live in the macrophage
- Th1 cell binds to macrophage via MHC
- Co-stimulation via CD40/CD40L
- Co-stimulation INF-y
- Bacteria fuse into phagolysosome
- Reactive oxygen species
- Nitric oxide production
- Killing pathogen
Th1 cells and tuberculosis
-Tuberculosis evolved to partially resist reactive oxygen species
- formation of granuloma (a lot of infected macrophages surrounded by a lot of Th1 cells which give IFN-y signal and are stopped from spreading)
- Control of TB
- Deficiencies in Th1 cells lead to poor control of TB
Th1 cells and autoimmunity and inflammatory disease
- MS
- RA
- T1D
- Psoriasis
- Crohn’s
- Allograft rejection
Th2 cells
- important for extracellular pathogens e.g. extracellular bacteria and helminth parasites
- Differentiation induced by IL-4
- Production of IL-4, which promotes B cells to class switch to IgE
- Secrete IL-4, IL-5 and IL-13
- Act on basophils, eosinophils and mast cells to promote resistance to parasites
- Involved in allergies, hay fever, asthma
Th17 cells
- Plastic subset, their phenotype depends on the environment, and they have the ability to become Th1 or Th2 if the cytokine environment changes
- Enhance neutrophil response
- Stimulate bone marrow to increase neutrophil production
- Promote barrier integrity (skin, intestine)
- Protection against fungi and mucosal infection by bacteria
- Involved in autoimmunity - MS, Crohn’s, RA
Th17 differentiation
- Differentiation is stimulated by IL-6, TGF-Beta, IL-1b and IL-21
- Stimulates transcription factors RORgammat and RORalpha
- Transcription factors activate the expression of IL-17, IL-17F, IL22 and CCL20
Function of Th17 cells
- IL-17 and IL-22 induce the production of antimicrobial peptides by epithelial cells
- IL-22 increases epithelial turnover (increased shedding impairs bacterial colonisation)
- IL-17 activates stromal cells to produce G-CSF to increase neutrophil production by the bone marrow
- IL-17 promotes infiltration of neutrophils into the site of the infection
- CCL20 is chemoattractant of other Th17 cells
How are Th17 cells plastic?
Downstream signalling from cytokine receptor activates transcription factors which upregulate expression of cytokines receptors
- IL-12 receptor consists of IL-12Rbeta1 and IL-12Rbeta2 subunits which lead to phosphorylation of STAT4 and expression of T-bet and IFN-y (Th1 cell)
- IL-23 receptor consists of IL-23R and IL-12Rbeta1 subunits which lead to phosphorylation of STAT3 and expression of RORgammat and RORalpha (Th17 cell)
- When there is not a lot of IFN-y in the environment the IL-23 will keep th17 phenotype but if the environment change and there will be a lot of IFN-y it will lead to upregulation of IL-12Rbeta2 which will pair with IL-12Rbeta1 and will become a th1 cell.
Tfh cells
- Differentiation mediated by IL-21
- Express BCL-6 transcription factor
- Express chemokine receptor CXCR5 to travel to follicles
- Germinal centres
- Co-stimulation of B cells with CD40/CD40L and cytokines IL-4 and IL-21
BCL-6
Master transcription factor of Tfh cells, it induces protein called SAP which is important for having adhesion molecules that allow the B cell and T cell to stabilise physical interaction.
Treg
- express Foxp3
- generated in the thymus or in the periphery
- pTreg differentiate in presence of TGF-B and retinoic acid (usually in the gut)
- important for controlling immune responses and to control immune response where it is not desired for example against the bacterial flora of the gut or dietary antigens
How Tregs regulate the immune response?
- they produce inhibitory cytokines (IL-10, TGF-beta, IL-35)
- cytokine consumption
- CTLA4
- cytotoxicity (perforin, granzyme) killing APCs etc.
