T cell activation and generation of effector T cells Flashcards
Summary of relevant concepts so far
T cell undergoes early developmental process in the thymus to generate T cells expressing clonal TCR
This TCR recognises antigen in the context of MHC
CD4 TCR recognises MHC II/peptide complex
CD8 TCR recognises MHC I/peptide complex
Self tolerance established
Self MHC restriction established
Mature but naïve T cell exported from the thymus in resting state but can recognise MHC
MHC class I presents endogenous antigen
MHC class 2 presents exogenous antigen
What professional antigen presenting cells activate T cells?
Dendritic cells- myeloid cells that are able to detect presence of infection- they get primed and activated. They phagocytose, process and present antigens in the context of MHC I and II molecules, and present those to T cells.
Macrophages can also act as antigen presenting cells.
B lymphocytes present to T cells to get help
Only activated professional antigen presenting cells express high levels of MHC class II. These antigen presenting cells also express co-stimulatory molecules
To be fully activated and differentiated into effector or memory T cell, the T cell needs 3 different signals- what are these?
Signal 1: Antigen recognition (TCR and MHC I and II)
Signal 2: Co-stimulation
Signal 3: Cytokines
What is antigen recognition?
Is the signal that initiates the immune response, so that the immune response is antigen-specific
TCR in T cell recognises the antigen in the context of MHC:
CD4 TCR recognises MHC II/peptide complex
CD8 TCR recognises MHC I/peptide complex
However extra accessory molecules are needed to succeed in inducing activation to the T cell
Where are the co-stimulatory signals that you need with antigen recognition to activate T cell?
Most commonly on dendritic cells
But may also be provided by macrophages or B cells
What do we know about co-stimulatory molecules?
TCR signaling is NOT enough to activate a naïve T cell
co-stimulatory molecules are also required:
1) B7:CD28
CD28 is expressed by the T cell
B7-1 (CD80) and B7-2 (CD86) molecules are expressed by the APC
What occurs as a result when T cells activate APCs via CD40?
T cells activate APCs via CD40 – CD40L interaction, enhancing T cell responses.
Upon activation, T cells upregulate CD40L, which binds to CD40 on DCs and stimulates the production of co-stimulatory molecules and cytokines by the DCs, thus enhancing T cell proliferation and differentiation.
What do negative co-stimulatory molecules do?
They inhibit the downstream effector processes initiated by TCR MHC/peptide interaction
Reduce inflammation after the infection has cleared
Not expressed by naïve T cells, there are induced upon activation
For example
CTLA-4 and PD-1, LAG3
PD-1: Programmed cell death protein 1.
Mainly expressed in T cells in peripheral tissues.
What do we know about Cytotoxic T-Lymphocyte Antigen 4: CTLA-4?
CTLA-4 is expressed approx 2-3 days post stimulation
It has high affinity/avidity for CD80 but opposing effects to CD28.
It is mostly expressed in T cells in secondary lymphoid organs.
Peak levels of expression lower than CD28 but avidity of interaction is much higher
Therefore, competes favourably with CD28 for ligation to CD80/86
What cytokines induce T cell polarisation?
Various forms of signal 3 induce the differentiation of naïve CD4 T cells down distinct effector pathways.
Each effector T cells expresses a master controller transcription factor
This transcription factor controls the expression of effector cytokines
cytokines include TGF beta, IL 6, IL12, IL4
What will a naive T cell do post TCR signalling?
Following successful signalling via the TCR, a naive T cell will:
1.Modify the expression of surface molecules
2.Upregulate cytokine production
3.Undergo active rounds of proliferation:
Upregulate expression of pro-survival genes
Upregulate expression of IL-2 and IL-2R-a
4. Differentiate into effector or
memory cells
What induces T cell polarisation into the different subsets?
The polarising cytokines
These are generated by the stimulating APC
Which cytokines they produce depends on:
The cellular origin of the APC
The maturation and activation status of the APC
Which pathogens or inflammatory mediators were encountered by the APC
In which tissue environment the encounter takes place
What do TH1 cells do?
These were the first identified subsets
TH1 polarisation occurs in response to the presence of intracellular pathogens such as viruses and bacteria that are ingested by and destroyed by phagocytes.
Master transcription factor that controls differentiation – T-bet
Function:
They produce IFNg
Help to activate macrophages to ingest and destroy microbes
Induce antibody class switching to IgG (opsonization).
All helpful response in eliminating an intracellular pathogen
What do we know about the development and function of TH2 cells?
Development:
TH2 polarization occurs in response to phagocyte - independent immune responses ie mostly parasites
TH2 polarizing cytokine is IL-4
Dendritic cells do not make IL-4
Eosinophils, basophils and mast cells produce IL-4. ILCs also produce IL-4
Transcription factors: IL-4 activates STAT6 which promotes expression of GATA 3
GATA 3 is a transcriptional activator of IL-4 and IL-13 genes
Function:
TH2 cells produce IL-4, IL-5 and IL-13, effector cytokines that help eliminate extracellular parasitic infections such as worms
Promote class switching to IgE, which causes inflammatory cytokines to be released by eosinophils and mast cells.
They also increase intestinal movement and mucus production.
IgE also mediates allergy
Summarise key concepts in lecture
T cells require close interaction with specific “professional antigen specific cells” to become activated
APC provide 3 signals – MHC-peptide-TCR, co-stimulatory molecules and cytokines
Co-stimulation induces positive and negative outcomes of activation, and these signals often compete
Co-stimulation and cytokine production are layers of regulation and specification of T cell activity
Armed-effector T cells produce effector cytokine that have an impact on the function of other immune cells
T cells differentiate into multiple functional subsets that can respond efficiently to different pathogens or inflammatory stimuli
T cell subset differentiation is flexible of “plastic” and T cells can switch polarising phenotype to a certain degree
