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 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:
- Modify the expression of surface molecules
- Upregulate cytokine production
- Undergo active rounds of proliferation:
Upregulate expression of pro-survival genes
Upregulate expression of IL-2 and IL-2R-a - 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
