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SEM 4: Immunology > T Cell Activation & Generation of Effector T Cells > Flashcards

T Cell Activation & Generation of Effector T Cells Flashcards

1
Q

What are the two types of adaptive immune response?

A
  1. Humoral Immunity

2. Cellular Immunity

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2
Q

What is humoural immunity?

A
  • Mediated by B lymphocytes and antibodies.
  • Targets extracellular pathogens
  • B cells mature in the bone marrow
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3
Q

What is cellular immunity?

A
  • Mediated by T lymphocytes
  • Targets intracellular pathogens
  • T cells mature in the thymus
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4
Q

What are the stages of T lymphocytes?

A
  1. T cells mature in the thymus
  2. They are generated in the bone marrow but mature in the thymus.
  3. Mature naive T cells are released from the thymus into the blood
  4. They recirculate between blood and peripheral lymphoid organs.
  5. When they encounter antigens, they recognise they activate a number of steps.
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5
Q

What are naive T cells important for?

A

They are less likely to lead to an autoimmune reaction but are very effective against a foreign antigen.

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6
Q

Give examples of peripheral lymphoid organs

A

Lymph nodes
Spleen
Mucosal associated lymphoid tissue (MALT)

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7
Q

What steps do antigens activate?

A
  1. Lymphocyte activation
  2. Lymphocyte differentiation
  3. Lymphocyte proliferation
  4. Lymphocyte differentiation into effector/memory cells
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8
Q

What are Effector T cells?

A

Have a specialised function mainly to eliminate the pathogen

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9
Q

What are Memory T cells?

A

Have memory responses which means they are faster and more efficient at destroying a pathogen that has been encountered previously.

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10
Q

What is the role of T cells in the immune response?

A
  • Designed to fight intracellular microbes such as:
    • > intracellular bacteria in phagosomes of phagocytes
    • > Viruses which are free in the cytoplasm of cells
    • > Cancer cells which are the cells that have mutated proteins.
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11
Q

When do T-cells recognise antigens?

A

Once they have undergone processing and presentation. Most T-cells recognise antigens in the form of peptides

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12
Q

What type of complex are the peptides in?

A

Recognise these foreign antigen peptides only when bound to major histocompatibility complex (MHC) molecules

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13
Q

What is the structure of the T cell receptors?

A

It has 2 chains: one alpha and one beta (most common TCR type)

  • Each chain has 1 variable domain (V domain) and 1 constant domain (C domain)
  • The antigen binding site is formed by Valpha and Vbeta
  • The V and C domains of TCR and BCR are homologous: more or less the same structure in a folded protein
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14
Q

What is the antigen binding site on the TCRs’ structure?

A

Made of a variable alpha and the variable beta towards the N terminal

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15
Q

What is the function of the antigen binding site on the TCR?

A
  • Scans and makes contact with the antigen
  • The variable regions have hypervariable, complementary determining loops (3 in each variable domain). These loops make the most contact with the antigen out of the whole variable domain.
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16
Q

What is the structure and function of MHC I?

A
  • Presents peptides to CD8+ (cytotoxic) T cells
  • Composed of an alpha cells and beta 2 macroglobulin
  • Expressed on all nucleated cells
  • Has HLA-A, HLA-B, and HLA-C. This is human lecocyte antigen which are important for transplantation.
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17
Q

What is the structure and function of MHC II?

A
  • Presents peptides to CD4+ (helper) T cells
  • Composed of alpha chain and beta chain
  • Only expressed on antigen presenting cells such as dendritic cells and macrophages
  • Has HLA-DP, HLA-DQ and HLA-DR
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18
Q

What is the difference between the MHC I and II?

A

The only difference is in MHC I, the 2 chains are alpha and B2 macroglobulin, whereas in MHC II, the 2 chains are alpha and beta.

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19
Q

How does TCR bind to the antigen via MHC?

A
  1. The peptide and the TCR variable domain come into contact in the groove formed by the MHC class I.
  2. The peptide comes in contact specifically with the hypervariable, complementary determining loops present in the variable domains of the TCR.
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20
Q

What are antigen presenting cells?

A

Cells that specialise in the capture and presentation of antigens to CD4+ T cells.

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21
Q

What are professional antigen presenting cells?

A

Cells that do not need to be activated to become APCs, some other cells such as B cells can be APCs but need to be activated first, which means they are not professional ones.

22
Q

Give examples of professional antigen presenting cells

A
  • Dendritic cells which are the only APCs capable of presenting to naive T cells
  • Macrophages which present to previously activated effector T cells.
23
Q

Which other cells do CD8+ T cells recognise antigens from?

A

Nucleated cells not just APC

24
Q

Where are dendritic cells found?

A

Found in the skin (called Langerhans in the skin), mucosa, tissue.

25
Q

What is the action of dendritic cells?

A
  1. They capture the microbes and transport them from the tissue to the draining lymph nodes.
  2. When they take them up, they process the microbes into antigens.
  3. They present the antigens to the naive T cells which activates them.
26
Q

What is the main function of dendritic cells?

A

They are critical in the initiation (priming) T cell responses

27
Q

How is the T cell response amplified?

A
  1. TCR will recognise the antigen on the MHC of APCs
  2. Co-stimulation is needed, this is the binding of co-stimulatory molecules CD80/86 (part of the B7 family) on the APC and CD28 on the T cell.
  3. Cytokines regulate the differentiation of activated T cells into different types of effector T cells.
28
Q

Why are co-stimulatory signals important?

A

Important to drive the signalling pathway that promotes survival, proliferation and differentiation (not just activation)

29
Q

What is the function of macrophage (APCs)?

A
  • Phagocytsoe microbes such as Mycobacteria tuberculosis
  • Antigen presentation to effector CD4+ T cells (Th1)
  • Activation of Th1 cells
  • Th1 cells activate macrophage to kill ingested microbes
30
Q

Which cells do nucleated cells present peptides to?

A

They present peptides derived from antigens in the cytosol to CD8 T cells; this is because all nucleated cells can get infected by viruses or become malignant.

31
Q

What are the specialisation of CD8+ T cells?

A
  • Recognise viral proteins and mutated proteins
  • Eliminate cells infected by viruses/malignant cells
  • Recognise antigens from phagocytosied microbes if these antigens escape from the phagosome into the cytosol (evade the immune system)
  • Main mechanism = kill infected cell via antigen specific contact
  • NOT kill uninfected healthy cells
  • Eliminate reservoirs of infection
32
Q

What are the two ways CD8 cells kill infected cells?

A
  1. Killing mediated by cytolytic molecules

2. Killing mediated by death receptor pathway (Fas/FasL)

33
Q

What are examples of cytolytic molecules?

A
  1. Perforin - forms pores that is a way of granzyme delivery
  2. Granzymes (A,B,C) - delivered to the site of contact between CD8+ and infected cell and initiates apoptosis, whilst preventing killing of neighbouring healthy cells
34
Q

Describe the process of exogenous antigens processing

A
  1. Exogenous antigens such as bacteria are taken up in the cells, get processed and presented by MHC II to CD4+ T cells
  2. The exogenous bacteria (bacteria that grows outside the cell) will get taken up by phagocytes and get eliminated by them.
  3. It gets eliminated by antibodies via neutralisation, opsonisation and complement activation.
  4. CD4+ T cells effectors help macrophages (Th1) and B cells (Th2) to eliminate extracellular bacteria.
35
Q

Explain the exogenous antigen processing in detail

A
  1. The macrophage (APC) takes up the bacteria into an endosome where the bacteria is broken down.
  2. The endosome will fuse with lysosome to form endo-lysosome where the low pH of the enzymes will cleave the protein and generate peptides (antigens).
  3. Whilst this is happening, the MHC II molecule (which is a protein) is being produced in the ER, from chains (a beta and an alpha).
  4. The MHC II will be unstable because the peptide groove is not coupled to anything yet, so it gets coupled by invariant chain which stabilises it, so it doesn’t breakdown.
  5. The MHC II molecule then leaves the ER, to the Golgi then into exocytic vesicles.
  6. The vesicle travels to the surface of the cells, where it enters the endo-lysosomal compartment (containing the antigen).
  7. The invariant chain stabilising the MHC II molecule, breaks down and only one small fragment called CLIP remains in the MHC II molecule.
  8. The endo-lysosomal compartment expresses another MHC II like molecule called HLA-DM which is not involved in antigen presentation.
  9. The CLIP molecule binds to HLA-DM meaning it is able to leave the MHC II so now the MHC II molecule can now bind to the antigen which stabilises it.
  10. The MHC II molecule fuses with the plasma membrane and can be scanned by CD4+ T cells that make contact with the infected cell.
36
Q

What is the role of HLA-DM?

A

Allows the CLIP molecule to leave the MHC II, so the peptide groove is empty for the antigen to attach. It does that by having high affinity for the CLIP molecule and so the CLIP molecule binds to it instead.

37
Q

Which antigens are presented to CD8+ T cells by MHC 1?

A

Cytosolic antigens such as viruses, mutated proteins in cancer cells get processed and presented by MHC I to CD8+ T cells.

38
Q

Explain the process of endogenous antigen processing

A
  1. The infected cell (can be APC or epithelial cell) will have the virus in the cytosol as well as the viral proteins.
  2. The viral infected cell will have proteasomes which gain specific units and become immunproteasomes, which are able to recognise foreign viral proteins present.
  3. These break down the viral proteins into peptides which are transported to the lumen of the ER via TAP transporter.
  4. The MHC I molecule is synthesized in the ER, and it contains a free groove.
  5. The antigen peptide will bind to the groove and stabilise it.
  6. This means the MHC I molecule is now able to leave to the golgi, then into exocytic vesicles.
  7. These then fuse with the plasma membrane and present the antigen on the surface to the CD8+ T cells.
39
Q

What are the types of effector T cells?

A
  • Helper cells
  • Cytotoxic T lymphocytes (CTL)
  • Regulatory T Cells (CD4+, CD25+, FOXP3+)
  • Cytokine release
40
Q

What are the helper cells?

A

Express CD4

  • Th1: help phagocytes to kill ingested microbes
  • Th2: help eosinophils/mast cells to kill helminths
  • Th17: role in defence against bacteria and fungi
  • Tfh: help B cells
41
Q

What are cytotoxic T lymphocytes?

A

Express CD8

- Kill cells infected with microbes but grow free in the cytosol

42
Q

What are regulatory T cells?

A

Immune tolerance and inhibition of immune responses

43
Q

Which cytokines induce the differentiation into Th1?

A

IL-12 and IFN-y

This is due to APC infected with bacteria such as mycobacteria and listeria

44
Q

Which is the main cytokine produced by Th1?

A

IFN-y

45
Q

What is the main role of Th1?

A

To activate phagocytes (macrophages) so destruction of intracellular pathogens can occur

46
Q

Which antibodies do Th1 stimulate the production of?

A

Stimulate the production of IgG antibodies by B cells, which increase phagocytosis of microbes

47
Q

Which cytokines induce the differentiation into Th2?

A

IL4, IL25 and IL33

Ones from APCs infected with helminths

48
Q

What are the main cytokines produced by Th2?

A

IL4, IL5 and IL13

49
Q

What is the main role of Th2?

A

To help B cells produce IgE. This helps opsonisation of helminths; activates eosinophils and mast cells; eosinophil and mast degranulation and killing helminths.

50
Q

Give an overview of CD4+ T cell responses

A
  • Naive T cell recognises antigens in the peripheral lymphoid organs
  • Activation, proliferation and differentiation into effector T cells occurs
  • Effector CD4+ T cells leave the activation site via the blood
  • Effector CD4+ T cell migrates to the site of antigen entry
  • Effector CD4+ T cell performs its effector functions to eliminate antigens together with other cells (macrophages, B cells)
51
Q

Give an overview of CD8+ T cell responses

A
  • Antigen recognition by naive CD8+ T cells in peripheral lymphoid organ
  • Activation, proliferation and differentiation into effectors occurs
  • Effector CD8+ T cell leaves activation site via the blood
  • Effector CD8+ T cell migrates to the site of antigen entry
  • Effector CD8+ T cell performs its effector function to eliminate antigen/infection

SEM 4: Immunology (15 decks)

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