T cell activation and generation of effector T cells Flashcards Preview

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Flashcards in T cell activation and generation of effector T cells Deck (33)
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1

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 

2

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) 

3

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

4

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

5

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 

6

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)

7

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

 

8

What is the only APC that can present to naive T cells? 

Dendritic Cells 

(Macrophages will present to previously activated effector T cells) 

9

Where are dendritic cells found? 

Skin (Langerhans cells), mucous membranes and lymphatic organs 

10

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

11

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

12

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 

13

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 

14

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 

15

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 

16

What does the type of cytokine released from the APC depend on? 

Depends on the infection and different cytokines result in different effector T cells produced 

17

What is the role of macrophages? 

  1. Phagocytose microbes (mycobacterium tuberculosis)
  2. Antigen presentation to effector CD4+ T cells (Th1)
  3. Activation of Th1 cells will help activate macrophages to increase their killing activity of ingested microbes

18

What are CD8+ T cells speciallised to do? 

  • Recognise viral antigens and mutated proteins 
    • Eliminate cells infected by viruses/ malignant cells 

19

Wha type of antigens do CD8+ T cells recognise? 

Endogenous antigens processed in the cytosol of infected/ malignant nucleated cells and presented on the surface through MHC I 

Also recognise exogenous antigens that have been phagocytosed if these antigens escape from the phagosomes into cytosol (cross-presentation) 

20

What type of antigens do CD4+ T cells recognise? 

Exogenous antigens taken up by cells and processed by MHC II to CD4+ T cells 

  • CD4+ T cell effectors help macrophages (Th1) and B cells (Th2) to eliminate extracellular bacteria
    • These cells will stimulate B-cells to produce the particular class switch antibodies for example IgG which is a potent opsin and will result in complement activation, or high affinity antibodies which have a better chance of neutralising the extracellular pathogens

21

Describe exogenous antigen processing 

  1. Dendritic cells/ phagocytes will ingest extracellular microbes e.g bacteria by phagocytosis/ receptor mediated endocytosis to form an endosome/phagsome 
  2. Endosome will fuse with lysosome to form a phagolysosome which will break antigens down into its peptides 
  3. MHC II proteins are produced ER and held by an invariant chain to stabalise the MHC II 
    1. The invariant chain contains a sequence called CLIP which binds to the peptide binding groove 
  4. MHC II will leave the ER and enter the golgi where it forms an exocytotic vesicle 
  5. Exocytotic vesicle will fuse with the late-endolysosome where the antigenic peptides are 
  6. Late endolysosome has a low pH, invariant chain will be broken down leaving CLIP in the MHC II groove 
  7. HLA-DM has a high affinity for CLIP removing it from the MHC II molecule 
  8. Antigenic peptides will bind to MHC II complex leaving the late endo-lysosome and fuses with the plasma membrane 
  9. Infected APC can now be recognised by TCRs on CD4+ T cells 

22

Describe endogenous antigen processing 

  1. Infected (virally or malignant) nucleated cell (can include APC) will produce viral/malignant proteins in the cytosol 
  2. These will be ubiquitinated and targeted to the proteasome which will recognise proteins and degrade them into peptides
  3. Peptides will be imported into the ER lumen via a transporter called TAP protein where there is MHC I production 
  4. Tapasin will link MHC I molecules to the TAP protein allowing antigens to be easily captured by MHC I molecules as they enter 
  5. MHC I with succesfully captured peptides will leave the ER and enter the golgi where they form exocytotic vesicles 
  6. Exocytotic vesicles will fuse with the plasma membrane which can be recognised by CD8+ cytotoxic T cells 

23

When can exogenous antigens be presented by MHC I? 

Exogenous antigens can under cross-presentation and be presented by MHC I when they escape the phagosome/endosome and enter the cytosol where they undergo endogenous processing and presentation by MHC I 

24

What are the different T helper cells adn their functions? 

Th1 = Help phagocytes kill ingested microbes 

Th2 = Help eosinophils/mast cells and B cells to kill helminths, also involved in allergic reactions 

Th17 = Role in defence against bacteria/fungi 

Tfh (T-follicular helper cells) = Help B-cells undergo class switching and affinity maturation 

25

What is the role of regulatory T cells? 

Immune tolerance and inhibition of immune response 

26

What do regulatory T cells express on their cell surface? 

CD4+, CD25+, FOXP3+ 

27

What cytokines induce differentiation of activated T cells into Th1 and by what cells are they produced? 

IL-12 and IFN-gamma 

Produced from APC infected with bacteria (e.g mycobacteria, Listeria) 

28

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 

29

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) 

30

Function of Th2 cells 

Produce cytokines IL-4, IL-5 and IL-13 which will help B-cells produce IgE 

  • IgE opsonise helminths 
  • Activate eosinophils and mast cells 
  • Eosinophil and mast cell degranulation and killing of helminths 

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