T cell activation and generation of effector T cells Flashcards
What are the life stages of T lymphocytes
- T cells are generated in the bone marrow and undergo maturation in the thymus (posotive and negative selection) producing mature naive T-cells
- Mature naive T cells are released from the thymus into the blood
- They circulate between the blood and peripheral lymphoid organs (lymph nodes, spleen and MALT)
- If they encounter specific antigens they recognise they will undergo lymphocyte activation, proliferation and differentiation into effector/memory cells
- Effector T cells = specialised functions to eliminate pathogens
- Memory T cells = memory responses
What type of microbes are killed by T-cells?
Intracellular microbes
- Intracellular bacteria in phagosomes of phagocytes
- Viruses: free in cytoplasm of cells (phagocytes or non-phagocytes e.g epithelial cells)
- Cancer cells (mutated proteins from cancer cells)
What is the requirement needed for T cells to recognise antigens?
T cells will only recognise antigens once they are processed and presented
T cells (αβ TCR T cells) recognise peptides
- Important to note à T cells γδ TCR will recognise antigens that are not peptides
What is the structure of the T cell receptor?
- TCR cells will recognise antigens via their TCR (T-cell receptor)
- The T cell receptor has a similar structure to the B cell antigen receptor (BCR)
- 2 chains: alpha and beta (most common) (can also be delta and gamma)
- Each chain has 1 variable domain and 1 constant domain
- Antigen binding site formed by Vα + Vβ
- V and C domains of TCR and BCR are homologous
- 2 chains: alpha and beta (most common) (can also be delta and gamma)
What are the two MHC molecules and what is their structure
- Display what is going on inside the cell e.g processed antigens
- MHC I = Presents peptides to CD8+ T cells
- MHC II = Presents peptides to CD4+ T cells
-
MHC I STRUCTURE
- alpha 1 and alpha 2 form peptide binding groove
- alpha 3 and beta-2-microglobulin form base
-
MHC II STRUCTURE
- Alpha 1 and Beta 1 form peptide binding groove
- Alpha 2 and Beta 2 form the base
Where are MHC I and II molecules expressed?
MHC I = Expressed on all nucleated cells
MHC II = Only expressed on APC’s (macrophages, dendritic cells, monocytes, B-cells)
What are MHC molecules also known as?
Human leukocyte antigens
There are several classes
- MHC I e.g HLA-A, HLA-B, HLA-C
- MHC II e.g HLA-DP, HLA-DQ, HLA-DR
- These are important in organ transplantation
What is the only APC that can present to naive T cells?
Dendritic Cells
(Macrophages will present to previously activated effector T cells)
Where are dendritic cells found?
Skin (Langerhans cells), mucous membranes and lymphatic organs
What is the role of dendritic cell?
- Capture microbe and process them forming antigens
- Transport microbes from tissues (e.g epithelia) to draining lymph nodes
- Present antigens to naïve T cells and activate them
What are the three signals that are required for dendritic cells to activate T-cells
- Dendritic cells are the only type of cell that activate naïve T-cells
- The naïve T-cell requires three signals for activation
- Signal 1 = TCR binding to MHC with peptide
- Signal 2= Co-stimulation CD80/CD86 (APC) binding to CD28 on T-cell
- Signal 3 = Cytokines will also be produced by dendritic cells; this will determine what type of effector T-cell response we will get depending on the infection
Explain how the three signals come about
- Signal 1 = In an infection there will be an increased antigen presenting function of APCs as more MHCs are expressed, TCRs will recognise the antigens
-
Signal 2 = In an infection there will be upregulation of CD80/86 (B7 family) which will then bind to CD28 molecules on T cells
- If we only have signal 1 then it will not be sufficient to activate T cells and the T-cell may become unresponsive/ anergic to that specific antigen (even if it were to meet it again)
- Signal 3 = Cytokines will be produced by APC regulate differentiation of T-cells into different effector T-cells
What happens if we only have signal 1 when a T-cell is activated by an APC?
If we only have signal 1 then it will not be sufficient to activate T cells and the T-cell may be unresponsive/ anergic to that specific antigen
If an APC that has presented to a naive T-cell releases IL-12 and IFN-gamma what type of T-cell should it differentiate into?
Th1 = Helps activate macrophages to increase their killing activity of ingested microbes
If an APC that has presented to a naive T-cell releases IL-4 what type of T-cell should it differentiate into?
Th2 = Helps eosinophils/mast cells and B cells to kill helminths (parasites) and also involved in allergic reactions
What is the role of macrophages?
- Phagocytose microbes (mycobacterium tuberculosis)
- Antigen presentation to effector CD4+ T cells (Th1)
- Activation of Th1 cells will help activate macrophages to increase their killing activity of ingested microbes
Describe exogenous antigen processing
- Dendritic cells/ phagocytes will ingest extracellular microbes e.g bacteria by phagocytosis/ receptor mediated endocytosis to form an endosome/phagsome
- Endosome will fuse with lysosome to form a phagolysosome which will break antigens down into its peptides
- MHC II proteins are produced ER and held by an invariant chain to stabalise the MHC II
- The invariant chain contains a sequence called CLIP which binds to the peptide binding groove
- MHC II will leave the ER and enter the golgi where it forms an exocytotic vesicle
- Exocytotic vesicle will fuse with the late-endolysosome where the antigenic peptides are
- Late endolysosome has a low pH, invariant chain will be broken down leaving CLIP in the MHC II groove
- HLA-DM has a high affinity for CLIP removing it from the MHC II molecule
- Antigenic peptides will bind to MHC II complex leaving the late endo-lysosome and fuses with the plasma membrane
- Infected APC can now be recognised by TCRs on CD4+ T cells
Describe endogenous antigen processing
- Infected (virally or malignant) nucleated cell (can include APC) will produce viral/malignant proteins in the cytosol
- These will be ubiquitinated and targeted to the proteasome which will recognise proteins and degrade them into peptides
- Peptides will be imported into the ER lumen via a transporter called TAP protein where there is MHC I production
- Tapasin will link MHC I molecules to the TAP protein allowing antigens to be easily captured by MHC I molecules as they enter
- MHC I with succesfully captured peptides will leave the ER and enter the golgi where they form exocytotic vesicles
- Exocytotic vesicles will fuse with the plasma membrane which can be recognised by CD8+ cytotoxic T cells
What is the main role of Th1?
- Produce IFN-gamma which activates macrophages
- Increases destruction of intracellular pathogens
- Stimulate B-cells to produce IgG
- Increases opsonisation and phagocytosis of microbes
What cytokines induce differentiation of activated T cells into Th2 and by what cells are they produced
IL-4, IL-25 and IL-33
Produced by APCs/cells infected with helminths (parasites)
What is the overview of the CD4+ T cell response
- Naive CD4+ T cells recognise antigens on dendritic cells in peripheral lymphoid organs
- T cell activation proliferation and differentiation into effector T cells (Th1/Th2)
- Differentiated CD4+ Th cells leave activation site and enter circulation
- Migration of effector T cells and other leukocytes to the site of antigen entry
- Effector function of T cells are carried out to eliminate antigens together with other cells
What is the overview of the CD8+ T cell response?
- Naive CD8+ T cells recognise antigens on dendritic cells in peripheral lymphoid organs
- T cell activation, proliferation and differentiation into effector T cell (cytotoxic T cells)
- Differentiated CD8+ cytotoxic T cells leave activation site and enter circulation
- Effector CD8+ T cell migration to site of antigen entry
- Effector CD8+ T cells perform their effector functions to eliminate antigen/infection
