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Block 6 - week 1 > Antigen recognition and the effect of T cells - Hudig > Flashcards

Antigen recognition and the effect of T cells - Hudig Flashcards

1
Q

List the 6 types of T cells.

A 
There are 4 types of Helper T cells.
1. TFH - these are follicular T helper cells located in follicles.
2. TH1
3. TH2
4. TH17
The other 2 types of T cells are:
5. Treg - regulatory T cells
6. CTL - these are CD8 cytotoxic T cells
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2
Q

What are the key surface markers on the different types of T cells?

A

All T cells have CD3 on their surface.

  1. T helper cells have CD4
  2. Treg cells have CD25 and CD4
  3. CTL T cells have CD8
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3
Q

What are the major functions of the different types of T cells?

A
  1. TFH - produce growth factors for B and T cells, B cell isotype switching, provide help for B cell antibody production
  2. TH1 - increase CTL activity, activate infected macrophages, provide help for B-cell antibody production
  3. TH2 - increase antibody production and mediate Bcell switch to IgE production
  4. TH17 - attract neutrophils
  5. Treg - regulate proliferation of normal T and B cell responses
  6. CTL - kill virus infected and stressed cells
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4
Q

Where are TFH cells and B cells located?

A

In lymphoid follicles in the spleen, lymph nodes and peyer’s patches. B cells are also located in tonsils and the appendix.

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5
Q

Describe TFH activation.

A
  1. An APC displays an antigen in MHCII that a TFH recognizes.
  2. The interaction with the APC allows the specific TFH to divide.
  3. The clones secrete IL-2 which is a growth factor for all T and B cells.
  4. Many antigen specific effector T cells are produced as well as T memory cells.
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6
Q

What is critical to the development of AIDS?

A

lack of CD4 T helper cells.

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7
Q

What major cytokines do the T helper cells produce?

A
  1. TFH - gIFN, IL-2,IL-4, IL-5
  2. TH1 - gIFN
  3. TH2 - IL-4
  4. TH17 - IL-17
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8
Q

Do TH1 cells secrete IL-4?

A

No, they secrete gIFN

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9
Q

Do TH2 cells secrete gIFN?

A

No, they secrete IL-4

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10
Q

Describe how TH1 and TH2 cells can polarize immune responses.

A

TH1 cells secrete gIFN and IL-2 which leads to increased CTL activity (drives cellular immune responses). CTL’s kill virus infected and stressed cells. TH2 cells secrete IL-4, IL-5 and IL-2. This leads to production of antibodies by B cells (drives humoral immune responses). So a TH1 driven response is more effective against virus but leaves the host more susceptible to other infections. A TH2 driven response results in lots of antibodies but leads to more susceptibility to virus.

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11
Q

What is the signature cytokine for TH1 cells?

A

gIFN

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12
Q

What is the signature cytokine for TH2 cells?

A

IL-4

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13
Q

What is the signature cytokine for TH17 cells?

A

IL-17

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14
Q

What affect does gIFN have on B cells?

A

It causes slow proliferation and supports B cell switch to IgG antibody production.

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15
Q

What does IL-4 cause?

A

Interleukin 4 is produced by macrophages and Th2 cells. It stimulates the development of Th2 cells from naïve Th cells and it promotes the growth of differentiated Th2 cells resulting in the production of an antibody response. It also stimulates Ig class switching to the IgE isotype.

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16
Q

What does IL-12 do and what cell types secrete it?

A

Dendritic cells and macrophages secrete IL-12 which directs a naive T helper cell differentiate into a TH1 cell.

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17
Q

What other type of cell secretes IL-4?

A

Mast cells can secrete Il-4 after they interact with anaphylatoxins from complement. This leads to naive T helper cells differentiating into TH2 cells.

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18
Q

Name a function of TH1 cells that a TH2 dominant response would be ineffective against.

A

TH1 cells control intracellular mycobacterium tuberculosis. This bacteria causes TB and antibodies are ineffective against it because it is intracellular.

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19
Q

What effect do memory TH1 cells have on macrophages?

A

CD4 TH1 cells secrete gIFN which allows the macrophage to make nitric oxide synthetase. This leads to the killing of bacteria inside the macrophage.

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20
Q

What is one mechanism by which CD8 CTL cells kill intracellular bacteria?

A

They contain an enzyme called perforin that makes a pore in the infected cells membrane. This allows an enzyme called granulysin to get in and kill the bacteria.

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21
Q

What cell type mediates delayed type hypersensitivity?

A

TH1 cells - this is our defense against bacteria that live inside macrophages.

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22
Q

Give examples of intracellular bacteria.

A

mycobacterium tuberculosis, M. leprae, listeria, salmonella, erlichia etc.

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23
Q

Can infected macrophages kill the bacteria inside them by themselves?

A

No, they need cytokine signaling from antigen specific TH1 cells.

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24
Q

How do delayed type hypersensitivity memory T cells develop?

A

Via antigen-specific proliferation - which requires primary exposure.

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25
Q

What is delayed type hypersensitivity?

A

It is a type IV hypersensitivity reaction. It can occur when a person was previously exposed to an antigen and makes memory T cells to that antigen. For example, If a person has had TB vaccine and is then tested for immune response against TB bacteria. The antigen is injected subcutaneously, memory TH1 cells made during the primary response are activated when macrophages display TB peptide. This takes time (24-48 hours). Inflammation is triggered and the site of the antigen injection becomes red and edematous.

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26
Q

What is the effect of high IL-4 on B-cells?

A

It drives them to switch to IgE production. IgE arms mast cells against helminths (worms).

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27
Q

What cytokines are critical for control of helminths?

A

IL-3, IL-9, These 2 cytokines released by TH2 drive mast cell recruitment.

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28
Q

What do mast cells produce?

A

Mediators such as histamine, TNF-a, and MMCP (a mast cell protease). These recruit inflammatory cells and remodel the mucosa.

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29
Q

What does TNF-a do?

A

Tumor necrosis factor alpha is produced by activated macrophages is response to microbes, especially the lipopolysaccharide (LPS) of Gram negative bacteria. It is an important mediator of acute inflammation. It mediates the recruitment of neutrophils and macrophages to sites of infection by stimulating endothelial cells to produce adhesion molecules and by producing chemokines which are chemotactic cytokines. TNF- α also acts on the hypothalamus to produce fever and it promotes the production of acute phase proteins.

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30
Q

What is the role of TH17 cells?

A

They provide bacterial immunity at epithelial/mucosal barriers.

31
Q

What cytokines cause differentiation of TH0 cells to TH17 cells?

A

IL-6 and TGFbeta along with a nuclear transcription factor - RORy.

32
Q

Describe the activation of a TH17 mediated reaction.

A
  1. Dendritic cells displaying antigen in MHCII molecules and secreting IL-6 and TGFbeta interact with a specific TH0 cell.
  2. The cytokines induce TH0 cells to become TH17 cells.
  3. TH17 cells secrete IL-17 which induces fibroblasts to secrete the chemokine CXCL8. This attracts neutrophils to phagocytose bacteria. IL-17 also interacts with keratinocytes and epithelial cells to produce inflammation.
33
Q

What do Treg cells do?

A

They suppress THelper cells and they suppress the cell division of all lymphocytes. Naive Tregs from the thymus interact with antigen presenting cells displaying peptide in MHCII. The Treg becomes activated and secretes suppressive cytokines.

34
Q

What cytokines do Treg secrete?

A

IL-10 and TGFbeta.

35
Q

What does IL-10 do?

A

It suppresses activated APC’s from making cytokines.

36
Q

What does TGFbeta do?

A

Reduces lymphocyte proliferation.

37
Q

What cell surface proteins do TH17 cells have?

A

CD4, CD25

38
Q

Do other cells have CD25 on their surface?

A

Yes, but only Tregs are CD25+ when released from the thymus. Other Tcells with the CD25 protein are CD25-

39
Q

What is CD25 a receptor for?

A

IL-2

40
Q

D Tregs secrete their suppressive cytokines constitutively?

A

No. Only after interaction with antigen.

41
Q

What would happen without Treg cells?

A

The lymph nodes and spleen would enlarge.

42
Q

Do Tregs stop the proliferation of just certain cell types?

A

It will stop the proliferation of ALL lymphocytes.

43
Q

What can happen when there is an overproduction of Treg cells?

A

Clinical anergy. Tregs secrete IL-10 which turns off gIFN production and they secrete TGFbeta which stops the proliferation of all lymphocytes. The result is that the body does not make T and B cell responses. For example a person with fulminant (out of control) TB can overproduce T regs and present with clinical anergy - they will have M. tuberculae in sputum but will have a negative skin test to TB antigen.

44
Q

What has to happen for CTL’s to be effective?

A

They must interact with antigen and proliferate and must receive cytokines such as IL-2. They lack granules when they are naive. They also lack FASL receptors.

45
Q

Do CTL’s differentiate into memory cells?

A

Yes, but they do not have granules until they are reactivated.

46
Q

What cytokines cause naiveCTL’s to differentiate into effector cells and gain cytotoxic mechanisms?

A

IL-2, IL-15 and/or IL-21

47
Q

What are two mechanism of CTL killing?

A

CTL’s become activated via antigen, proliferate and become effector CTL’s. They bind to the specific antigen on the infected cell and release Perforin. Perforin forms pores in the cell membrane and leads to cell death via necrosis/lysis or it lets in cytotoxic substances from granule exocytosis. Another way is for the CTL to cause apoptosis via the TNF receptor family (FASL on CTL and FAS on infected cell).

48
Q

What is perforin?

A

Perforin is an enzyme that is only found in CTL’s and NK cells. It causes pore formation in the lipid by- layer of membranes which leads to cell death either by necrosis and lysis or by letting in cytoxic substances.

49
Q

Describe the various ways a CTL can stop viral replication?

A
  1. it may use gINF to induce the infected cell to degrade the viral mRNA -leaving the cell alive and cured
  2. it may kill the cell by either necrosis or apoptosis
50
Q

What is necrosis?

A

involves damage from outside the cell that leads to cell death

51
Q

What is apoptosis?

A

a form of cell death where a cell is induced to commit suicide and dies from the inside out. The plasma membrane stays intact around cell fragments and these blebs are are cleared by phagocytic cells. In apoptosis of a virus infected cell the virus remains contained.

52
Q

What is contained in CTL granules?

A

Perforin, granzyme A, granzyme B, other granzymes and granulysin. Perforin is needed for the granzymes and granulysin to enter the cell. Granzymes A and B act as proteases that cleave death-promoting substrates leading to apoptosis.

53
Q

What other cell type has granules with perforin and granzymes?

A

NK cells

54
Q

How do CTL’s recognize only infected targets?

A

The MHCI of infected cells will display microbe antigens and the MHCI of uninfected cells will be displaying self peptides.

55
Q

What types of cells do CTL’s target?

A

They target viral infected cells but granulysin contained in their granules can also kill bacteria. Either way, they only kill intracellular viruses and intracellular bacteria.

56
Q

What types of vaccines are effective against viruses?

A

Only CTL’s can control viral proliferation and only a vaccine that contains live virus can induce a CTL response. Only a live virus that can get inside a cell can be have its peptides displayed by MHCI. This is why some vaccines against viruses need a booster - to increase CTL and prevent infection.

57
Q

Are antibodies effective against viruses?

A

no

58
Q

What is diGeorge syndrome?

A

A syndrome in which a malformation of the 3rd and 4th pharyngeal pouches leads to abnormal development of the thymus, parathyroid glands and heart. Pt’s will have low T or no T cells, low calcium, tetany, and heart damage. Patients with low T cells do have antibodies. They are very susceptible to viral infections, mycobacterial and fungal infection. Any live virus vaccine would be contraindicated for these patients.

59
Q

What is dual recognition?

A

T cell receptors (TCR’s) must be specific to the peptide displayed by MHC and they must be able to recognize the MHC.

60
Q

What Tcell surface molecules act as recognition signals?

A

CD3, and CD4/CD8

61
Q

If a self cell is not infected what is displayed in its MHCI molecule?

A

An MHCI will not be on the cell surface if it does not have antigen in it. If a cell is uninfected it will hold self peptides in its MHCI. T cells generated with anti-self TCR’s are deleted or are made unresponsive.

62
Q

How long is the antigen peptide held in an MHCII molecule?

A

About 20-30 amino acids long. MHCII molecules hold peptides for CD4 T-helper cells.

63
Q

Describe MHCII.

A

It is a dimer made from an alpha and a beta chain with a binding site (made of parts of both alpha and beta chains) that recognizes thousands of different peptides.

64
Q

Describe MHCI.

A

It has a single alpha chain and one beta chain. The alpha chain forms the cleft that binds peptide and the beta chain is invariant. The binding site can recognize thousands of different peptides. Any peptides larger than 11 AA’s long will not fit into the MHCI cleft.

65
Q

What re CD4 and CD8?

A

They are co-receptors for MHC molecules. They initiate signaling via kinases when the TCR binds tightly.

66
Q

What is CD1?

A

These are proteins found only on APC’s that are structurally similar to MHC. They display bacterial lipid antigens such as those from TB. Responding T cells are CD4-/CD8- cells.

67
Q

What do both CD4 and CD8 T cells need in order to be activated and mount a response?

A

They need to signals. The first is they need to be able to recognize the antigen and MHC, the second is a co-stimulatory signal. The co-stimulatory signal for T cells is the binding of B7 on the APC with CD28 on the T cell. If both signals are there then the APC will secrete TNF-a and IL-1 to initiate the immune response.

68
Q

What is B7 and where is it found?

A

B7 also called CD80 or CD86 is a co-stimulatory molecule that is located on APC’s and activated B cells.

69
Q

What happens when T cells get only signal 1?

A

They die or become anergic. This is called peripheral tolerance.

70
Q

Do B cells need a signal 2?

A

Yes but it is different.

71
Q

How are B and T cell receptors similar?

A
  1. they both consist of two chains
  2. they both have variable regions where antigen binds at the end of the receptor
  3. they both have short intra-cytoplasmic tails
  4. they both have molecules that perform transmembrane signaling.
72
Q

How are B and T cells different?

A
  1. B cells have antibody receptors that recognize native antigen structures
  2. T cell receptors recognize processed proteins (peptides)
  3. T cell receptors are unchanged in AA sequence for the life of the cell (no affinity mutation)
  4. B cells may later secrete proteins (antibodies) that are similar to their antigen receptors
  5. only B cells undergo gene mutation for affinity maturation of the receptor and antibody
  6. Co-stimulatory receptors and their counter ligands differ for T and B cells
73
Q

What are the signals for B cells?

A
  1. antigen

2. CD40 on B cells binds to CD40L on activated T cells

Block 6 - week 1 (11 decks)

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