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MICB 202 > T Cells of Adaptive Immunity > Flashcards

T Cells of Adaptive Immunity Flashcards

1
Q

What are the two main weapons of adaptive immunity?

A

Antibodies and T cells

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2
Q

What do T cells defend against?

A

T cells are the main defense against viral infections and bacterial pathogens that cause intracellular infections (e.g., Mycobacterium tuberculosis).

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3
Q

What is TCR?

A

The T cell receptor (TCR) is a membrane-bound protein composed of two different polypeptides known as the α chain and the β chain.

The two chains are joined together by a disulfide bond.

There are no secreted forms of the TCR.

Expression of the TCR involves rearrangement of TCR “gene segments” to form a complete gene. This happens for both chains. Therefore, each T cell has its own “version” of the TCR and thus has unique antigen specificity.

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4
Q

What forms the antigen-binding site on a TCR molecule?

A
  • The TCR α and β chains expressed at the cell surface each have one variable (V) region and one constant (C) region.
  • The Vα and Vβ chains regions combine to form the antigen-binding site.
  • There is only one antigen-binding site per TCR molecule.

A single, mature T cell will have approximately 30,000 identical copies of the TCR on its cell surface.

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5
Q

What does the TCR complex of a mature T cell consist of?

A

An antigen-binding portion that is comprised of the TCR α and β chains, plus an associated signaling subunit (CD3 complex) and accessory proteins (either CD4 or CD8, but not both).

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6
Q

What does the TCR antigen-binding subunit recognise? What doesn’t it recognise?

A

Peptides that are bound to MHC proteins. It does not recognise native, intact (unprocessed) antigens.

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7
Q

What causes proliferation of a T cell?

A

The signaling subunit (CD3) of the TCR sends signals to the inside of the T cell that activates it and causes it to proliferate.

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8
Q

What defines the effector function of a T cell?

A

The co-receptors CD4 and CD8.

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9
Q

Where are CD4 and CD8 found?

A

CD4 is found on T helper cells whereas CD8 is found on cytotoxic T cells.

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10
Q

Where do CD4 and CD8 bind?

A

CD4 and CD8 bind to the MHC proteins on the antigen-presenting cell, but not at the site involved in peptide binding.

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11
Q

What does contact between CD4 or CD8 and MHC proteins increase?

A

Increases the affinity of interaction between the T cell and the antigen-presenting cell.

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12
Q

What does the CD4 co-receptor recognize?

A

A conserved region (not involved in peptide binding) of MHC class II proteins.

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13
Q

What does the CD8 co-receptor recognize?

A

A conserved region (not involved in peptide binding) of MHC class I proteins.

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14
Q

What are CD3 proteins and how are they activated?

A

The CD3 proteins are signaling proteins that are activated once the TCR has recognized antigen.

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15
Q

What are CLPs?

A

Some progeny of the HSCs start to “specialise” into common lymphoid progenitors (CLPs) that can further differentiate into T cell precursors that leave the bone marrow environment and travel to the thymus to complete their maturation.

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16
Q

What are T cell precursors?

A

Thymocytes

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17
Q

How do thymocytes proliferate?

A

The thymocytes proliferate and differentiate along developmental pathways that eventually generate functionally distinct T cell populations.

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18
Q

Do T cell precursors express a TCR?

A

T cell precursors (known as thymocytes) do not express a TCR.

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19
Q

What must a developing thymocyte do in the thymus in order to survive?

A

Begin to express a TCR on its cell surface in order to survive

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20
Q

How are major stages of developing thymocytes tracked?

A

By changes in expression of the TCR, as well as of CD4, CD8, and other proteins.

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21
Q

What screening processes are thymocytes expressing TCRs subjected to?

A

Positive-selection and negative-selection.

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22
Q

What mediates positive selection?

A

Positive selection is mediated by thymic cortical epithelial cells.

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23
Q

What mediates negative selection?

A

Negative selection is mediated by bone marrow derived macrophages and dendritic cells, and medullary thymic epithelial cells (mTEC).

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24
Q

What is a double positive thymocyte?

A

DP = double positive, a immature thymocyte that is expressing both CD4 and CD8.

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25
Q

Where do T cell precursors that leave the bone marrow travel for maturation?

A

T cell precursors that leave the bone marrow environment and travel to the thymus to complete their maturation.

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26
Q

Which thymocytes are permitted to mature during positive selection?

A

Only thymocytes that have a TCR capable of weakly binding to MHC proteins of thymic cortical epithelial cells (displaying self-peptides) are permitted to mature.

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27
Q

What does positive selection ensure?

A

When a thymocyte matures into a T cell, its TCR will be able to bind to MHC proteins displaying foreign peptides.

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28
Q

What happens to thymocytes that have a TCR that cannot bind to MHC proteins?

A

Thymocytes that have a TCR that cannot bind to MHC proteins (displaying self-peptides) are not provided with survival signals and die of neglect

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29
Q

How many “rounds” of negative selection are thymocytes subjected to following positive selection, and what mediates each one?

A

Two total.

First is mediated by bone marrow derived macrophages and dendritic cells.

Second is by thymic medullary epithelial cells.

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30
Q

Which thymocytes are signalled to undergo apoptosis during negative selection?

A

Thymocytes that have TCRs that bind to MHC and self-peptide with high affinity receive a signal to undergo apoptosis.

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31
Q

What does negative selection test for?

A

Self-tolerance: if the recognition of MHC with self-peptide activated the T cells, then autoimmune disease could result.

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32
Q

What is the consequence of thymic selection?

A

Only a small fraction (less than 5%) of thymocytes develop into mature T cells.

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33
Q

Which thymocytes are permitted to mature into functional T cells?

A

Only thymocytes that have TCRs that bind to MHC (displaying self-peptides) with weak affinity.

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34
Q

Where do functional T cells migrate after they leave the thymus?

A

Peripheral lymphoid organs (lymph nodes and spleen)

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35
Q

T cells that survived positive and negative selection can be potentially activated by […] ?

A

MHC displaying foreign peptides because the TCR would recognise the foreign peptide displayed by the MHC protein with higher affinity.

36
Q

What does negative selection ensure?

A

Ensures mature T cells are not self-reactive.

37
Q

How can negative selection be achieved against antigens that are normally expressed outside of the thymus?

A

More recent studies have shown that there is an autoimmune regulator (AIRE) gene that promotes the expression of a wide variety of tissue antigens, including those not typically associated with the thymus (the AIRE gene encodes a transcription factor).

This second round of negative selection is by thymic medullary epithelial cells.

38
Q

Production of what type of cell is involved in regulating the activity of self-reactive T cells that have somehow escaped negative selection?

A

A special type of T cell called a T regulatory (Treg) cell.

39
Q

What is development of Treg cells in the thymus throught to be dependent on?

A

Relatively high affinity interactions with self-antigens

40
Q

How do Treg cells generated in the thymus differ from conventional T cells?

A

By expressing high levels of CD25 (one part of the receptor for IL-2).

41
Q

Can Treg cells be developed outside of the thymus?

A

There are also mechanisms for the development of different types of Treg cells outside of the thymus, and these cells are not necessarily specific for self-antigens.

42
Q

How are Treg cells unique?

A

They prevent conventional T cells from mounting immune responses.

The mechanisms by which they suppress these responses are currently a very active area of research.

43
Q

What is the antigen recognised by the T cell receptors of mature CTLs and T helper cells?

A

T-cell receptors do not recognize antigen in its native state, as do the immunoglobulin receptors of B cells, but recognize a composite ligand of a peptide antigen bound to an MHC molecule.

44
Q

Where does T cell selection take place, and what does it select for?

A

In the thymus and selects for TCRs that work (positive selection), but are not self-reactive (negative selection).

45
Q

What are CTLs and what do they do?

A

Killer T cells; they express CD8 and recognise MHC class I.

46
Q

What is the function of T helper cells?

A
  • Help other immune cells
  • express CD4
  • recognise MHC class II
47
Q

What defines the structure and function of helper T cells and of cytotoxic T cells?

A

The co-receptors CD4 and CD8 define the effector function of the T cell:

  • CD4 is found on T helper cells
  • CD8 is found on cytotoxic T cells
48
Q

T cell receptors (TCRs) are found exclusively on T cells.

True or false?

A

True

49
Q

Cytotoxic T cells express the CD8 protein as a co-receptor.

True or false?

A

True

50
Q

T cells undergo immune selection. T cells that gain access to the circulation have been screened for the ability to recognize MHC proteins and against strong reactions to self-antigens.

True or false?

A

True

51
Q

Self-reactive T cells are eliminated during the development of tolerance in the immune system.

True or false?

A

True

52
Q

The T cell receptor is made of one copy of the β chain and one copy of the α chain.

True or false?

A

True

53
Q

CD3 is the signalling component of the T cell receptor complex.

True or false?

A

True

54
Q

A mature T cell has both CD4 and CD8 proteins on the cell surface.

True or false?

A

False

55
Q

A T cell receptor complex in a mature T cell has one copy of the β chain, one copy of the α chain, the CD3 protein, and the CD4 or CD8 co-receptor.

True or false?

A

True

56
Q

The TCR of a thymocyte must be able to interact with an MHC protein in order for the thymocyte to escape apoptosis.

True or false?

A

True

57
Q

If the TCR of a thymocyte binds MHC very tightly, it will be positively selected and retained.

True or false?

A

True

58
Q

Almost all thymocytes pass positively selection, very few however, pass negative selection.

True or false?

A

False

59
Q

Treg cells help to control the self-reactivity of T cells that have somehow escaped negative selection.

True or false?

A

True

60
Q

The AIRE gene encodes a transcription factor.

True or false?

A

True

61
Q

The AIRE gene product allows medullary thymic epithelial cells to display peptides derived from proteins normally expressed by cell types outside of the thymus environment.

True or false?

A

True

62
Q

Where are precursor T cells derived?

A

Precursor T cells are derived from lymphoid precursor cells in the bone marrow - they migrate to the thymus to continue their maturation and start to express the TCR and other proteins.

63
Q

What are the two main types of effector T cells?

A

CD4 T helper cells

CD8 T killer cells

64
Q

Which peptides do CD4 T helper cells recognize?

A

peptides presented on MHC class II proteins

65
Q

Which peptides do CD8 T killer cells (or cytotoxic T lymphocytes, CTL) recognize?

A

peptides presented on MHC class I proteins

66
Q

What does the co-receptor CD4 or CD8 do?

A

strengthens the interaction between the antigen-presenting cell and T helper cell

67
Q

What does αβ TCR recognize in antigen recognition?

A

Aa complex of the MHC and peptide

68
Q

What is the role of CD3 (γε, δε, ζζ subunits)?

A

Relays a signal to nucleus that TCR has been engaged, triggers new gene expression

69
Q

How does CD3 signal?

A

CD3 and p56lck: p56lck is a kinase - adds phosphate groups to proteins (from ATP)

70
Q

What determines how a T cell matures?

A

The TCRs interaction with the MHC determines whether it matures into a CTL or T helper cell.

71
Q

What is the goal of positive selection of developing T cells?

Why is this important?

What does positive selection depend on?

What does positive selection select for?

A

Goal: Identify developing T cells that can bind to MHC proteins

Importance: APCs present peptides in complex with MHC; if T cell can’t interact with MHC, it can’t be activated.

Depends on: low affinity interactions between TCR and MHC + selfpeptide.

Selects for: T cells that are be potentially useful for developing immune responses against foreign antigens, particularly pathogens.

72
Q

What cells mediate positive selection of developing thymocytes?

A

The thymic cortical epithelial cells

73
Q

What is the goal of negative selection of developing T cells?

What is the importance?

What does negative selection depend on?

A

Goal: Identify developing T cells that bind MHC + self-peptide a little too tight.

Importance: T cells that bind MHC + self-peptide too tightly may be activated in the lymph node/spleen; could result in autoimmune disease.

Depends on: high affinity interactions between TCR and MHC + selfpeptide - these cells must be eliminated to maintain tolerance to self.

74
Q

What cells mediate negative selection in the thymus?

A

Bone marrow derived antigen-presenting cells

75
Q

How many candidate thymocytes actually pass positive and negative selection?

A

Less than 5% of candidate thymocytes actually pass positive and negative selection – most fail at the positive selection stage.

76
Q

What is the goal of positive and negative selection of thymocytes?

A

Get rid of the useless – those T cells that have TCRs that can’t interact with MHC because these cells could never be activated.

Get rid of the dangerous – those T cells that have TCRs that recognize MHC + self peptide strong enough to activate the T cell.

Keep only the ones that are potentially useful.

They might be able to recognize MHC and pathogen peptide with sufficiently high affinity to be activated.

77
Q

Where is the AIRE gene expressed?

A

The autoimmune regulator (AIRE) gene is expressed in thymic medullary epithelial cells.

78
Q

What does the AIRE gene do?

A

The AIRE gene product is involved in transcriptional regulation - it allows the expression of a wide variety of tissue-specific antigens in the thymus.

AIRE allows for negative selection against tissue specific antigens

(i.e., so you don’t have T cells that amack your heart, kidney, insulin producing islet cells)

79
Q

What happens to T cells with TCRs that cannot interact with MHC?

A

T cells with TCRs that cannot interact with MHC would be useless: these cells get no survival signal - default pathway is apoptosis.

80
Q

What happens to T cells with TCRs that interact with MHC and self-peptide strongly?

A

T cells with TCRs that interact with MHC and self-peptide strongly are dangerous: these cells are signaled to undergo apoptosis (programmed cell death).

81
Q

What happens to T cells with TCRs that interact with MCH and self-peptide weakly?

A

Only T cells with TCRs that interact with MHC and self-peptide weakly are allowed to mature: these cells may be able to recognize MHC and pathogen peptide with sufficiently high affinity to be activated.

82
Q

How are Treg cells different?

A

These T cells are “different” – somehow encouraged to be self-reactive and are not negatively selected during T cell development in the thymus.

83
Q

What is IL-10?

A

a “calming” anti-inflammatory cytokine

84
Q

What is the function of T regulatory cells?

A
  1. Shuts down self-reactive cells in the periphery: - prevents conventional T cells from mounting immune responses.
  2. “Resets” anergic cells: - so that they may be activated during infection. - gives cells a ‘second chance’

A deficiency in Tregs is correlated with an increased incidence of autoimmune disease.

Tregs are upregulated in some instances of cancer – shuts off the immune response to tumour cells.

85
Q

What is an anergic lymphocyte?

A

Lymphocytes are said to be anergic when they fail to respond to their specific antigen.

86
Q

What medical condition does the nude mouse model for?

How is this condition treated?

A

DiGeorge syndrome - several genetic mutations can cause this condition.

Patients will have hair, but may have other serious health problems: e.g., heart defects, seizures, hypocalcemia.

Treatment - transplantation of a thymus graft

MICB 202 (25 decks)

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