T cell activation and generation of effector T cells

Question 1

What are the life stages once a naïve mature T-cell is formed?

Answer 1

1. Naïve mature T cell.
2. Antigen recognition.
3. activation, proliferation and differentiation into effector T cells.
4. memory T cells.

Question 2

Where are naïve T-cells activated?

What does it produce?

Answer 2

Naïve T cells are activated in secondary lymphoid organs: spleen and LNs

Effector T-cells -> site of infection to eliminate infection

Question 3

To be fully activated and differentiated into effector or memory T cell, the T cell needs 3 different signals

What are these 3 signals?

Answer 3

• Signal 1: Antigen recognition
• Signal 2: Co-stimulation
• Signal 3: Cytokines from APCs – Part 3

Question 4

What does the Antigen recognition signal do?

Answer 4

• 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:
o CD4 TCR recognises MHC II/peptide complex
o CD8 TCR recognises MHC I/peptide complex

Question 5

Where is the co-stimulatory signal?

Why do we have co-stimulatory signals?

Answer 5

• Most commonly on dendritic cells
• But may also be provided by macrophages or B cells

• TCR signaling is NOT enough to activate a naïve T cell

Question 6

What is the first co-stimulatory signal?

Answer 6

B7:CD28
• CD28 is expressed by the T cell
• B7-1 (CD80) and B7-2 (CD86) molecules are expressed by the APC

Question 7

What does CD40 and CD40L do?

Answer 7

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.

Question 8

What does the Negative co-stimulatory molecules do?

Answer 8

• 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.

Question 9

What is Cytotoxic T-Lymphocyte Antigen 4: CTLA-4 and what is the function of it?

Answer 9

• 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

Question 10

What does signal 3 do?

What does IL-2 do?

Answer 10

• Various forms of signal 3 induce the differentiation of naive 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

• IL-2 is a growth, survival and differentiation factor for T cells and Tregs.

Question 11

What are the consequences of these signals and interactions?

Answer 11

The cells differentiate and proliferate to there effector functions.

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

Question 12

What induces T cell polarisation into the different subsets?

What are the factors for which type of cytokines are produced?

Answer 12

• The polarising cytokines
• These are generated by the stimulating APC
• Which cytokines they produce depends on:
o The cellular origin of the APC
o The maturation and activation status of the APC
o Which pathogens or inflammatory mediators were encountered by the APC
o In which tissue environment the encounter takes place

A number of different CD4 helper subsets have been identified with different functions

Question 13

Why does Th1 polarisation occur?

What is the function of Th1 cells?

Answer 13

• TH1 polarisation occurs in response to the presence of intracellular pathogens such as viruses and bacteria that are ingested by and destroyed by phagocytes.

• 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

Question 14

Why does Th2 polarisation occur?

What is the function of Th2 cells?

Answer 14

• TH2 polarization occurs in response to phagocyte - independent immune responses.
• TH2 polarizing cytokine is IL-4
o Dendritic cells do not make IL-4
o 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

• 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