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BoD > Adaptive Immune System > Flashcards

Adaptive Immune System Flashcards

1
Q

what are different agents of pathogens

A 
viruses, bacteria, fungi
and parasites (protozoa and helminths)
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2
Q

What is a BCR

A

B cell receptor - the surface receptor of a B lymphocyte

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3
Q

What do BCRs recgonise importantly

A

molecules in their natural conformation

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4
Q

where are BCRs generated

A

Bone marrow

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5
Q

what happens once BCRs are activated

A

the clones differentiate into plasma cells which secrete antibody or immunoglobulin

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6
Q

what is immunoglobulin

A

a soluble version of the BCR

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7
Q

define antigen

What do they interact with

A

anything that can bind to an Ab

epitopes - small parts of molecules

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8
Q

what are linear epitopes

A

When antibodies recognise

consecutive amino acids within a protein or peptide

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9
Q

will conformational epitopes always be apparent

A

they may only appear in the molecules native 3D form

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10
Q

describe the variable and constant regions of an antibody (briefly)

A

variable: N terminal - interacts a with antigen
constant: recruits effector function

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11
Q

what can the constant region of an antibody recruit/ interact with

A

receptors on cells such as dendritic cells, macrophages, neutrophils, basophils
and mast cells and can interact with complement.

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12
Q

What are the 3 ways that a antibody works

A

neutralisation
opsonization
complement activation

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13
Q

Describe the neutralisation caused by an antibody

A

Blocking the biological
activity of a target molecule e.g. a toxin to
its receptor.

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14
Q

Describe the opsonisation activity of an antibody

A 
Antibody coated antigen
interacts with specific receptors (Fc
receptors) on various cells, including
macrophages and neutrophils allowing
them to "recognise" antigen more
efficiently. Antibody functions as an
opsonin and phagocytosis is greatly
enhanced.

If the antibody activates complement, this will add to the opsonisation as well as directly lysing the molecules

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15
Q

Where are T cells generated

A

generated in the bone marrow but mature in the thymus

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16
Q

Give an overview of what happens to T cells in the thymus

A

the genes
encoding the T cell receptor (TCR) rearrange to generate clones of T cells with different
receptor specificity.

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17
Q

Can T cells recognise native proteins

A

No - while being structurally related to Immunoglobulins, T cells can only recognise degraded proteins when they are complexed with MHC molecules on neighbouring cells

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18
Q

what does MHC stand for

A

major histocompatability complex

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19
Q

what does antigen processing do

A

generates the peptides for display by antigen

presenting cells

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20
Q

What are the 2 classes of T cell

A

class I restricted and class II restricted

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21
Q

What do Class I Restricted T cells do

What do they mature into

What are they important for

A

recognise MHC Class I:peptide complexes and express the co-receptor CD8

Cytotoxic T cells

viruses and tumour cells

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22
Q

What do class II restricted T cells express

What do they do

Where are they predominantly expressed

A

CD4

Provide help for cytotoxic T cells and B cells

antigen presenting cells (APCs)

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23
Q

Name some APCs

A

dendritic cells, macrophages and B cells

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24
Q

When can Class II molecules be presented on non-APCs

A

They can be induced on other cells in the presence of IFN gamma

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25
Q

What are lymphocytes derived from ?

A

hematopoietic stem cells via a common lymphoid progenitor

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26
Q

What are naive cells

Why are they called this

A

T and B cells with successfully
rearranged receptors

they have not yet been exposed to their particular antigen and been activated

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27
Q

What do lymphocytes do in primary lymphoid organs

A

rearrange their receptors

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28
Q

What role do naive lymphocytes take on once released from the primary lymphoid organs

A

patrol and respond

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29
Q

How many lymphocytes pass through a lymph node each day

A

2.5x10^10

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30
Q

What % of the lymphocyte pool is recirculated each hour

A

1-2%

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31
Q

What are the lymph nodes and spleen designed to do

A

optimise interaction between APC and lymphocytes

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32
Q

Describe the course of lymphatic fluid

A

lymphatics drain fluid (containing dendritic cells and antigens) from tissue into lymph nodes

Lymph is collected by afferent lymphatics to pass through macrophage lined sinuses - here antigens can be captured and prevented from passing on into the blood

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33
Q

Why is the spleen different from lymph nodes

A

no direct connections to the lymphatic system

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34
Q

What does the spleen do

A

collects antigen from the blood and deals with immune responses to blood-borne pathogens

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35
Q

How do lymphocytes enter lymph nodes from the blood

A

through specialised endothelia (high

endothelial venules)

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36
Q

What do dendritic cells when they arrive at the lymph node from the periphery

A

enter the T cell area and present the antigen they have captured on MHC

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37
Q

Where do some B cells congregate

A

in B cell areas around follicular dendritic cells

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38
Q

How do FDCs trap antigens

What happens once the antigen is trapped?

A

in the form of antigen/antibody/C3b
complexes on their surface

hold it for long periods of time for B cells to screen - B cells with the highest affinity are induced to undergo affinity maturation

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39
Q

What does localisation of

APCs, B cells and T cells in the lymph node do

A

maximises the chance of successful B-T cell cooperation.

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40
Q

Do all B cells produce antibodies?

A

only produced by B cells that differentiate into plasma cells

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41
Q

Are Ab always bound to cells

A

They may be free in plasma, bound to cells by specific (Fc) receptors, or present in secretions such as milk, mucus and sweat

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42
Q

What does the constant domain of the Ab do

A

allow the
antibody to interact with other immune system effector cells and molecules such as macrophages
and complement and are said to recruit effector function

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43
Q

How are the heavy and light chains of antibodies held together

A

by covalent (disulphide bridges) and non-covalent forces

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44
Q

What are both heavy and light chains of Ab constructed of

A

Ig fold domains

light: 1 constant and 1 variable

Heavy: 1 variable, and three (IgG, IgA and IgD) or four (IgM and IgE) constant domains.

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45
Q

How can the main classes of Ig be distinguished

A

by their heavy chains denoted the Greek version of their Ig letter

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46
Q

Which part determines the function of the Ig

A

heavy chain

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47
Q

What gives the Ab flexibility

A

hinge region

V-C junction

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48
Q

What is the VC junction often compared to

A

a ball and socket joint

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49
Q

What is the antigen binding site formed by

how is variation concentrated

A

interaction between heavy and light chain variable
domains

three complementarity determining
regions or CDRs

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50
Q

Which is the most variable CDR

A

CDR3

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51
Q

How do CDRs appear

A

as 3 loops at the surface, forming a variable surface for interaction with the antigen

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52
Q

What part of the loops of the CDRs do antigens bind to

A

Antigens can bind in tight pockets, grooves or on extended surfaces which form the antigen
binding site of the molecule.

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53
Q

How many different antibody specificities do humans have?

A

10^11

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54
Q

What is the first stage of diversity generation in Ab

What is this

A

somatic recombination

gene rearrangement in B cell development

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55
Q

How many variable gene segments does the human heavy chain locus encode

What are these segments responsible for?

How many gene segments for diversity and for junctional

A

38-46

variation in CDR1 and 2

D: 23
J: 6

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56
Q

What generates variation in CDR3

A

rearrangements of VDJ segments

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57
Q

How are heavy chains arranged

A

1st: D->J
2nd: V–>DJ

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58
Q

What is allelic exclusion

A

Heavy chain rearrangement can occur on both chromosomes but if a functional heavy chain is
generated then rearrangement on the other chromosome is prevented

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59
Q

How many heavy chains can a single B cell express

A

only 1

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60
Q

How many diversity segments do light chains have

A

None

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61
Q

Light chains have no diversity segments. How do they recombine to generate diversity

A

rearrange kappa chain first then if unproductive rearrange delta chain

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62
Q

What enzymes are involved in somatic recombination

A

RAG1 and 2

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63
Q

What sequences are conserved in rearrangement during diversity generation in b cells

A

conserved heptamer, nonamer and spacer sequences located adjacent to
V, D and J segments.

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64
Q

What are the 4 main processes to generate Ab diversity

A
  1. Different heavy and light chain combinations
  2. Selection of different heavy V, D and J segments.
  3. junctional diversity
  4. somatic hypermutation
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65
Q

What is junctional diversity

A

Variable addition and loss of nucleotides at VDJ junctions

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66
Q

What order does junctional diversity occur in

A

Addition by TdT (to N terminal)
Addition due to the recombination mechanism (P-nucleotide addition).
Deletion of nucleotides

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67
Q

What is TdT

A

terminal deoxynucleotidyl transferase

enzyme that performs N-nucleotide addition in junctional diversity

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68
Q

What is somatic hypermutation

A 
Point mutations are introduced into heavy and light chain
variable regions. This involves deamination of cytosine to uracil by the enzyme
Activation Induced (Cytidine) Deaminase
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69
Q

What is AID used in

A

deamination of cytosine to uracil in somatic hypermutation

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70
Q

What happens to Ab with increased affinity after hypermutation

A

selected for by affinity maturation

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71
Q

What is the mutation rate of somatic hypermutation

A

1 per 1000 base pairs

per cell division.

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72
Q

What do T helper cells do generally?

A

s activate the B cells to produce antibody,

generally of relatively low affinity (IgM)

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73
Q

What is one model for the interaction between B cells and T follicular helper cells?

A

B cells that by chance have higher affinity for antigen will interact with FDCs bearing that antigen.
They can capture and present the antigen to a T follicular helper cell (TFH). It is these B cells that will receive help from the TFH cell and be stimulated to survive and predominate

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74
Q

mature B cells usually present which Ig isotypes?

How are these generated?

Can they change their isotype?

A

IgM and IgD

IgM and IgD are coexpressed and are generated by alternative splicing

yes via class/isotype switching

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75
Q

What choice determines whether an Ig will be soluble or membrane bound while still having the same VDJ specificity?

A

different poly-A sites

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76
Q

What are the 5 human Ig isotypes?

A

IgM, IgG, IgA, IgD and IgE,

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77
Q

Which Ig isotypes are split into subclasses?

What are the subclasses?

A

IgG and IgA

IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2

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78
Q

What determines most of the the effector function of an antibody?

A

Fc receptors

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79
Q

What do Fc receptors do

A

deliver the antibody to different anatomical

sites and link antigen to molecules or cells that effect its destruction.

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80
Q

What controls recruitment of effector cells

A

Differential expression

of Fc receptors by the effector cells

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81
Q

What are 2 key differences between Fc receptors

A

affinity

valency

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82
Q

How do affinity and valency affect Fc receptors

A

some are of high affinity and bind monovalent

antibody/antigen complexes while others are low affinity receptors and only bind multivalent antibody/antigen complexes.

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83
Q

What is the Kd of a high and low affinity Fc receptor

A

high: 10^-9
low: 10^-6

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84
Q

Give 2 monovalent Fc receptors

A

Fc (gamma)RII and III

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85
Q

Give 1 multivalent fc receptor

A

Fc (gamma) RI

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86
Q

What do the differences in affinity and valency provide for different Fc receptors

A

different levels of sensitivity to cells expressing the different receptors.

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87
Q

What do macrophages and neutrophils express to aid opsonisation

A

Fcg receptors which efficiently
recognise the Fc region of IgG antibodies,
particularly IgG1

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88
Q

What happens when the Fc gamma receptors on macrophages and neutrophils interact with antibodies?

A

leads to
phagocyte activation and results in enhanced
antigen uptake and degradation

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89
Q

Which Ig activates complement very effectively?

Name a receptor that recognises it efficiently?

A

IgM

the C3b receptor

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90
Q

What is the purpose of binding of antigen/antibody
complexes by C3b receptors present on red blood
cells

A

allows delivery of the complex to the liver and spleen for removal by macrophages

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91
Q

What is ADCC

A

Antibody dependent cell mediated cytotoxicity

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92
Q

Name 3 cells which express Fc (gamma) RIII

A

Natural killer cells,
neutrophils,
eosinophils

(also phagocytes)

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93
Q

What does Fc (gamma) RIII recognise?

A

it is a low affinity receptor that recognises only Ab/antigen complexes

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94
Q

What does ligation of the Fc (gamma) RIII on NK cells do

A

triggers release of cytoplasmic granules

containing lytic enzymes.

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95
Q

Can free Ig trigger ADCC

A

no - requires complexes of
antibody and antigen to provide multiple Fc
regions for recognition.

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96
Q

Which granulocyte mediates a unique type of ADCC?

Describe

A

eosinophils - to fight helminths

IgE binds to the surface of
worms. It signals through FceRI on the eosinophil to
release granules containing proteins that
are toxic to helminths.

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97
Q

What receptors do mast cells and basophils express and what do they recognise

A

FceRI and FcgRIII for IgE and IgG.

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98
Q

Why do mast cells and basophils have 2 types of Fc receptor

When is a similar response also elicited

A

Crosslinking of these receptors signals
release of inflammatory mediators into
surrounding tissues.

during allergic reactions
when allergens bind to IgE on mast cells

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99
Q

How long does degranulation of basophils and mast cells take?

What is released?

A

seconds

vasoactive amines such as
histamine and lipid and cytokine mediators
of inflammation such as, prostaglandins,
leukotrienes and TNF-a

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100
Q

Which 2 Ig protect mucosal surfaces from infection

A

IgA and to a lesser extent IgM

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101
Q

How does IgA cross the epithelial layer on mucosal surfaces?

A

A receptor for
polymeric Ig recognises the J chain region of IgA
and transports it across the epithelial cell.

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102
Q

Which Ig is important in milk for infants

A

IgA (this is the enzyme that crosses mucosal surfaces)

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103
Q

What do antibodies do in the gut of infants

A

IgA from breast milk remains in the gut and prevents

attachment of bacteria and toxins to gut epithelia.

104
Q

Which antibody is important for fetal protection?

A

IgG

105
Q

How does IgG cross from the mother to the fetus?

A

neonatal Fc receptor transports maternal IgG
across the placenta directly into the blood stream of
the fetus and provides high-level protection against
pathogens common in the environment at birth

106
Q

How do ruminants (NOT humans) acquire IgG

A

postnatally from colostrum via an IgG-specific

receptor in the gut

107
Q

How do B cells shut down Ab responses?

A

Ab produced in response to antigen
binds and forms immune complexes. B cells specific for the same antigen can bind
these immune complexes with both
Fc(gamma)RIIB and the BCR.

This acts as a
negative signal and terminates B cell
responses

108
Q

Which Fc is important in terminating an Ab immune response?

A

Fc(gamma)RIIB

109
Q

How do Fc(gamma) RIIB receptors help control inflammatory responses?

A

by antagonising the activity of activatory Fc receptors

110
Q

Which cells express FcgRIIB

A

many including macrophages, neutrophils, eosinophils and mast cells.

111
Q

What does the affinity of the Ab refer to ?

A

e interaction between a single antibody binding site

and a single monovalent epitope on an antigen

112
Q

How many antigen binding sites does an Ab have

What do they do with these sites?

A

at least 2

often bind to two epitopes on the same antigen

113
Q

What is avidity

A

a measure of the strength

of interaction due to recognition of polyvalent epitopes

114
Q

Describe the affinity and avidity of IgM

A

low

affinity but bind with high avidity

115
Q

What is the Major Histocompatibility complex (MHC)?

A

a large genetic locus on chromosome 6 that
codes for MHC class I and class II molecules and many other proteins involved in the
processing and presentation of antigens to T cells.

116
Q

What are MHC class I and II molecules?

A

cell surface glycoproteins whose function is to present

peptides to T cells

117
Q

Give an overview of the structure of MHC class I molecules

A

made from a transmembrane heavy or alpha

chain, which is non-covalently linked to b2-microglobulin.

118
Q

Describe the heavy chain of the MHC class I molecule

A

has three extracellular domain a1, a 2 and a 3.
The membrane distal domains (a1 and a 2)
form a peptide binding groove. The base of the groove consists of a beta pleated sheet and two alpha helices form the sides.

119
Q

What can the peptide binding groove of the heavy chain of MHC class I molecules accomodate?

A

peptides that are often 8-9 amino

acids in length

120
Q

What is the size of the heavy chain and the beta2 microglobulin in MHC Class I molecules?

A

heavy chain: 45kDa

beta2 microglobulin: 12kDa

121
Q

How does the structure of MHC class II relate to class I molecules?

A 
MHC class II molecules have a very similar structure but are made from two similar sized
transmembrane chains (a 33kD and b 30kD).

The peptide binding groove is formed by the a1
and b 1 domains and is supported by the membrane proximal a2 and b2 domain

122
Q

True or false:
Antibodies and T cell receptors show great binding specificity

How does this compare to MHC molecules?

A

True

A single MHC molecule in
contrast is able to bind a broad range of peptides composed of different amino acid
combinations

123
Q

What do the pockets in an MHC class I binding groove do?

What is the point?

A

interact with amino acid side chains of the
peptide.

It makes important interactions with the amino and carboxy terminus of the peptide
and this places restrictions on the length of peptide that can be accommodated

124
Q

Can peptides longer than 8-9 amino acids fit into the binding groove in MHC Class I molecules

A

yes if bent in the middle

125
Q

How does the MHC class II binding groove differ from that of the class I ?

A 
The class II peptide groove is open ended and can
bind longer peptides 13-25 amino acids, in an extended conformation.
126
Q

Generally, what is MHC diversity due to

A

polygeny and polymorphism

127
Q

What are MHC molecules also known as?

A

Human Leukocyte Antigens (HLA)

128
Q

What is polygeny in MHC diversity?

A 
the expression of multiple independent loci encoding class I and class II
genes
129
Q

What are the different isotype of each class of MHC molecule?

A

3 of each

class I :HLA-A, HLA-B and HLA-C

class II: HLA-DP,
HLA-DQ and HLA-DR
130
Q

What are the most polymorphic genes known

A

MHC genes

131
Q

How many Class I MHC alleles are there?

How many proteins does this refer to?

A

13,680 Class I alleles corresponding to 9,341

protein variants

132
Q

By how many amino acids can MHC alleles differ by?

A

between 1 and 50

133
Q

MHC genes are the most polymorphic genes known. Is this normal

A

This extensive allelic polymorphism is

thought to be pathogen driven and is unique to the MHC.

134
Q

Describe MHC inheritance

A

MHC loci are closely linked genetically and, in most cases (97%), are inherited together as sets
of alleles or haplotypes

alleles are co-dominantly expressed

135
Q

What does it mean to say MHC alleles are co-dominantly expressed

A

t both maternal and

paternal haplotypes are expressed together on the same cell

136
Q

How common is it to be homozygous for MHC alleles

A

In outbred populations
polymorphism at each loci makes it virtually impossible for two individuals to express the same
combination of MHC alleles

137
Q

Why is it better to be heterozygous for MHC alleles

A

Heterozygotes can present more peptides and activate more T cells than homozygotes.

138
Q

Where is polymorphism concentrated in MHC molecules

A

in the peptide binding domain and the domain that interacts with the TCR

139
Q

What will the TCR see of the MHC

A

a combination of a

particular MHC molecule associated with a particular peptide (MHC restriction)

140
Q

Can a TCR respond to the same peptide presented by different MHC molecules

A

this is very unusual due to MHC restriction

141
Q

What are anchor residues (MHC)

A

conserved amino acids at a certain position of a peptide

they anchor the peptide to the binding groove

142
Q

What do anchor residues determine

A

the peptide binding motif of a particular MHC

143
Q

Why can a single MHC molecule present a range of peptides?

A

Amino acids at non-anchor positions are not under the same strict constraints and may vary
considerably

144
Q

What are MHC molecules occupied by in the absence of infection?

A

self peptides

145
Q

Why does peptide presentation require a balance in binding characteristics? (2)

A
  1. If a large number of different peptides can bind only a few copies of any particular peptide-MHC combination will be presented at the cell surface.
  2. If a small number of different peptides can bind, many copies of the same peptide-MHC will be present at the surface. However pathogens with a small genome may not have a suitable peptide for presentation by the host’s MHC molecules
146
Q

Typically a cell with 100,000 MHC class I molecules of a single allotype presents how many different peptides?

A

1000

147
Q

What fraction of random peptides are able to bind a particular MHC allele?

A

Roughly 1/1,000-1/10,000

148
Q

An individual peptide-MHC complex can present how many molecules per cell?

What is the mean/

A

roughly 1-5,000 molecules per
cell

mean=100

149
Q

What is the range of MHC-peptide complexes that can activate a T Cell

A

from a single complex up to a few thousand

150
Q

Describe the genetic associations of MHCs with autoimmune diseases and with infectious diseases

A

many strong genetic associations with autoimmune disease but

associations with infectious disease are much weaker

151
Q

Why do we use chickens to explore the development of MHC molecules?

A

they have a single dominantly expressed MHC class I molecule

152
Q

Compare promiscuous and fastidious MHC class I molecules in chickens

A

Promiscuous: bind a wide range of peptides and give more or less protection against a wide range of pathogens.

Fastidious: bind fewer peptides and confer either resistance or
susceptibility to a given pathogen

153
Q

What happens to promiscuous and fastidious chicken MCHI alleles after infection

A

After infection with Marek’s Disease Virus (MDV) the percentage of promiscuous chicken MHCI haplotypes (B21 and B2) in the flock increases substantially.
Fastidious chicken MHCI haplotypes (B12-B19) are greatly reduced or eliminated

154
Q

Why would fastidious chicken MHCI haplotypes be reduced after MDV infection?

A

they were unable to find viral peptides to

present

155
Q

How have MHC moleules developed to counter both intra and extra cellular infections?

A 
MHC class I molecules present peptides from endogenous proteins e.g. viral proteins. 
MHC class II molecules present peptides from exogenous proteins e.g. bacterial proteins.
156
Q

What are MHC CI molecules designed to do?

A

present peptides from within the cell to CD8 cytotoxic T

cells

157
Q

What primarily degrades proteins within the cytosol

What happens to the products?

A

proteasome

moved to ER via TAP

158
Q

How are peptides from the proteasome moved to the ER

What happens to the peptides in the ER

A

via the Transporter associated with Antigen Processing (TAP)

 Peptides of suitable length and
sequence are loaded onto partially folded class I molecules in a complex process that is assisted
by a range of chaperone proteins assembled into a Peptide Loading Complex
159
Q

What happens to fully loaded MHC peptide complexes in the ER

A

they are released from the chaperones, pass through the golgi, and follow
the secretory pathway to the cell surface.

160
Q

How can the Peptide Loading complex (PLC) be visualised practically/

A

by single-particle electron cryo-microscopy

161
Q

Describe the MHC Class I antigen processing pathway

A

virus infects cell and antigen enters proteasome

  • -> peptides from proteasome go to ER via TAP
  • -> Suitable peptides are loaded on to partially folded MHC CI by PLC
  • -> fully loaded MHC CI released and passes through golgi to cell surface
162
Q

True or false

MHC Class I molecules have to pass through the ER during biosynthesis

A

False
MHC class II (NOT 1) molecules have to pass through the ER during their
biosynthesis.

163
Q

What prevents MHC CII binding to peptides as it passes through the ER

A

a/b chains associate with a third

component invariant chain (Ii)

164
Q

Give the 3 actions of the invariant chain of the MHC CII molecule as it passes through the ER

A

a) blocks the peptide binding groove
b) acts as a folding chaperone
c) targets class II/Ii complexes into the endocytic pathway.

165
Q

Where do the MHC CII molecules pass after the ER

A

Golgi to be sorted un to the endocytic pathway

166
Q

What happens to MHC CII in the endocytic pathway

A

Invariant chain is partially removed, leaving CLIP in the binding groove.

within the MIIC compartment CLIP is removed and the appropriate antigen derived peptides are loaded on to empty MCH CII with help from HLA-DM

167
Q

What helps loading of appropriate antigen derived peptides onto MHC CII in the endocytic pathway

A

the class II related molecule HLA-DM.

168
Q

What is the path of the MCH CII molecule after it has been loaded in the MIIC compartment during the endocytic pathway?

A 
MHC class II/peptide complexes are transported to the cell surface for presentation to CD4
T cells, but the pathway used is unknown
169
Q

Does the MHC locus only have Class I and II genes

A 
no
the MHC encodes other components of the antigen processing machinery:
HLA-DM 
HLA-DO
2 LMP components of the proteasome
TAP1 and 2 and TAPBP
170
Q

What are the 7 genes included in the MHC that are not the classical Class I and II genes

A

HLA-DM
HLA-DO
2 LMP components of the proteasome
TAP1 and 2 and TAPBP

171
Q

What are HLA-DM and -DO involved in?

A

regulating peptide presentation by MHC class II molecules.

172
Q

What is TAPBP

A 
TAP Binding Protein (aka Tapasin) -Like TAP1 and 2, is involved in peptide generation, peptide transport and peptide loading onto
MHC class I molecules.
173
Q

The genes for TAP1, TAP2, and TAPBP are located near which MHC class region?

Expand

A

MHC Class II

This is surprising because they are involved in peptide generation, peptide transport and peptide loading onto
MHC class I molecules (NOT CLASS II)
174
Q

Are T cells important in humoural or cell mediated adaptive immunity?

A

both

175
Q

How are the main 2 subsets of t cells distinguished?

A

d by
expression of different co-receptor molecules CD4 and CD8, their effector function and MHC
restriction

176
Q

What is the TCR encoded by

A

wo polypeptide chains each containing a constant and a

variable region

177
Q

What are individual domains of a TCR related to in the Ig?

A

the Ig fold domain

178
Q

What is the immunoglobulin superfamily?

A

Molecules containing Ig like domains are members of the immunoglobulin superfamily.

179
Q

Give the 4 key ways TCRs differ from BCRs

A

the TCR:
a) is monovalent
b) is membrane bound and does not have a secreted counterpart
c) does not undergo somatic hypermutation
d) is used solely for antigen recognition and is not linked to effector
function

180
Q

What are the stages of TCR rearrangement

A

1) Germline rearrangement
2) beta chain rearrangement
3) alpha chain rearrangement
4) non-template P and N nucleotides added to both alpha and beta chains

181
Q

describe germline reshuffling in TCR diversity generation

A

RAG1/2 stimulated by thymosin etc in thymus to shuffle DNA for TCR (different VDJ arrangement in α and β chains) and for CD8 and CD4

182
Q

What are the enzymes stimulated to reshuffle TCR DNA? What molecule stimulates them?

A

RAG1/2 stimulated by thymosin etc in thymus to shuffle DNA

183
Q

What happens in the beta chain reshuffle stage of TCR diversity generation

A

Dβ->Jβ, then Vβ->DJβ.
This is then presented on the surface with the surrogate α. This is double negative stage when both CD4- and CD8- are expressed

184
Q

What happens with non template nucleotides in TCR diversity generation?

A

final stage
o Nontemplate P and N nucleotides are added to both β-chain (VDJ) and α-chain (VJ) junction and αβ chains are displayed = double positive – selection can now begin

185
Q

Are RAG1 and 2 used in BCR diversity?

A

Yes used in both TCR and BCR diversity generation

186
Q

After rearrangement of the TCR DNA what will the exons now code for

A

a leader sequence, a VDJ region, a constant region

and a transmembrane region

187
Q

What is the most variable region of the TCR

What does it do

Where is it focussed?

A

CDR3

CDR3 makes
the major contact with peptide present in the
MHC groove.

VDJ junction

188
Q

What are the 3 things T Cells are selected for?

A

1) successful β chain rearrangement
2) positive selection
3) negative selection

189
Q

What is the aim of T cell selection

A

to “eliminate the harmful and reject the useless”.

190
Q

What % of double positive T cells survive

A

2%

191
Q

What does negative selection of T cells do

A

prevent autoimmunity by deleting autoreactive cells

192
Q

What does positive selection of T cells do

A

ensures that peripheral

T cells will be useful since cells that cannot recognise self MHC cannot become activated.

193
Q

Do B Cells undergo positive selection

A

no

Positive selection is unique to T cells.

194
Q

How does positive selection of T cells work (3 stages)

A

Newly rearranged T-cell receptors are tested against self
peptide/MHC complexes expressed on cortical epithelial cells.

TCRs with a “moderate
affinity” for self MHC/peptide receive a positive signal to continue maturation. Lack of
interaction results in death by neglect.

Expression of CD4 and CD8 co-receptors is altered to
match MHC restriction. Cells that survive will be CD4+ single positive if selected against
MHC class II/peptide or CD8+ single positive if selected against MHC class I/peptide.
195
Q

What happens to thymocytes
expressing TCRs with a “high” affinity for
MHC/self peptide

A

eliminated from the

repertoire by apoptosis

196
Q

Which T cells are not affected by negative selection

A

Negative selection can not
eliminate T cells with receptors recognising
MHC/peptide combinations that are not
expressed in the thymus

197
Q

Negative selection can not
eliminate T cells with receptors recognising
MHC/peptide combinations that are not
expressed in the thymus. How are these dealt with?

A

by mechanisms that operate in the periphery

198
Q

How do T cell precursors progress through the thymus?

A

bone marrow precursors
enter the outer sub-capsular region and progress towards the medulla
through the cortex.

199
Q

What cells mediate positive selection of T cells in the thymus

Where are they found

A

cortical epithelial cells

cortex of the thymus

200
Q

Describe the cortex of the thymus

A

densely packed with immature rapidly
dividing T cells (thymocytes). These cells continue rearranging their α chain gene segments
giving multiple opportunities for positive selection

201
Q

What is the major cause of thymocyte death?

A

lack of positive selection

202
Q

Name 3 cell types present in the medulla of the thymus

A

Medullary epithelial cells

bone marrow derived dendritic cells

macrophages

203
Q

Which cells are most efficient at triggering negative selection in T cells

A

Bone marrow derived cells (dendritic cells and

macrophages)

204
Q

What are macrophages important for in the medulla of the thymus

A

removing thymocytes that fail to mature

205
Q

What happens to t cells that survive selection in the thymus

A

enter the circulation as mature naïve T cells and take up a life of
patrol and respond. They must be activated by a professional APC to become functional.

206
Q

Can mature naive t cells recognise MHC/peptide complexes?

A

yes
Mature naïve T cells have TCRs capable of recognising MHC/peptide complexes but require
additional stimulation to become activated

207
Q

What is the 2 signal hypothesis

A

signal 1 is

delivered by TCR engagement and co-stimulatory molecules deliver signal 2

208
Q

What does CD28 do

A

molecule on t cell which interacts with molecules on the APC

delivers co-stimulation to t cell needed for t cell activation

209
Q

What is CD40L

A

a molecule on the t cell that would interact with CD40 on the APC

210
Q

What is a defining feature of professional APCs?

A

Expression of costimulatory molecules

211
Q

name 3 professional APCs

A

DCs,

Macrophages and activated B cells

212
Q

Where are dendritic cells found

What do they do

A

in most tissues

, take up antigen in the infected tissues and
are activated by TLRs and CD40 receptors. They increase MHC class II synthesis and begin to
express co-stimulatory molecules (B7.1 and B7.2) at the cell surface.

213
Q

What do DCs do once they have their antigen cargo?

A

migrate to draining lymph nodes where they remain and present antigen to
circulating T cell

214
Q

How do naive t cells enter the lymphoid organs?

A

through specialised endothelial cells

high endothelial venules

215
Q

Do naive t cells remain in a lymph node once they reach one?

A

no
They continually circulate through lymph nodes and back to the
blood, making contact with thousands of APCs every day

216
Q

What induces a naive T cell to proliferate

What do they proliferate and differentiate into ?

A

Binding of
MHC II:peptide complexes by the TCR and CD28 by B7

an expanded population of armed effector T helper cells.

217
Q

How does a B cell become fully active?

A

must interact with armed effector T helper cells

218
Q

Describe the interaction between b cell and helper t cell

A

B cell binds and internalizes antigen via surface Ig (signal 1)

antigen is processed and presented as MHC class II/peptide complex (this complex is identical to original presented by DC)

CD28 and CD40L on the T cell to bind B7 and
CD40 on the B cell.

Cross-linking of CD40 on the B cell (B cell activation signal 2) promotes
B cell proliferation, provides B cell survival signals and promotes immunoglobulin class
switching.
219
Q

Is Interaction between B cell and T cell co-stimulatory molecules important

A

yes

it is essential and leads to mutual activation (B-T cell co-operation).

220
Q

What are the co stimulatory elements expressed on b and t cells ?

Which binds to which?

A

T: CD28/CD40L
B:B7/CD40

CD28-B7
CD40L-CD40

221
Q

What is the 3rd cell-cell interaction of the primary antibody response

A

the binding of activated B cells to follicular dendritic

cells

222
Q

What are FDCs (3)

A

follicular dendritic
cells
specialised stromal cells that hold intact, i.e. unprocessed, antigen on their
surface in the form of long-lived immune complexes. They are only present in B cell follicles
and enable the activated B cell to form germinal centres.

223
Q

What has the intrinsic ability to stimulate naïve B cells without the need for
B cell/T cell interaction

A

thymus independent

antigens (TI antigens)

224
Q

What are TI antigens typically?

A

microbial products composed of repetitive
elements (polysaccharides and lipopolysaccharides) which cross-link membrane Ig and induce
B cell proliferation.

225
Q

What are CD8 T cells destined to become?

What about CD4 t cells?

A

cytotoxic T cells

Naïve
CD4 (Th0) cells can differentiate into distinct subsets (originally described as Th1 or
Th2), depending upon the nature of the antigenic challenge and the cytokines present during
proliferation

226
Q

What do Th1 cells do

A

produce cytokines that support inflammation and cell mediated responses

227
Q

What is the signature TF of Th1 cells

A

T-BET

228
Q

What infections are Th1 cells important for

A 
intracellular pathogens (e.g.
mycobacteria).
229
Q

What cells do Th1 cells mainly activate?

A

macrophages,

NK cells and CTLs

230
Q

What do Th2 cells do

A

activate immune responses that assist in the elimination of

parasitic infections.

231
Q

What is the transcription factor for Th2

A

GATA3

232
Q

What are Th17 cells involved in

transcription factor?

A

defence against extracellular bacteria and fungi

RORγT

233
Q

What are Tfh cells?

A

Follicular helper T cells

essential promoting antibody responses

234
Q

What is the TF for Follicular helper T cells

A

BCL-6

235
Q

What are Tregs

A

T cell suppressors -suppress the activity of other T cells

236
Q

Transcription factor for Tregs

A

FOXP3

237
Q

When does the differentiation into Th1 or 2 subsets occur?

Why is this important to note

A

early in immune response

, cytokines
produced by cells of the innate immune system (including dendritic cells, macrophages, ILCs
and NK cells) play a vital role in focusing the immune response

238
Q

Does amount of antigen affect immune response?

A

abundance of antigen,
MHC/peptide concentration and T cell receptor affinity also influence the response. Abundant
antigen and high affinity TCR interactions favour TH1 responses and low peptide abundance or
with weak affinity for TCR favour TH2 responses

239
Q

Why is it important to get Th1/2 decisions right early

A

bias towards one or the other becomes self reinforcing

240
Q

Which t cell pathway leads to cell mediated immunity

What does it do

A

The TH1 pathway

It
increases inflammation to defend against
intracellular bacterial, viral and protozoan infections

241
Q

What does the Th2 pathway do

A

humoral immunity

promotes production of pathogenspecific IgE antibodies that work with basophils,
mast cells and eosinophils to control parasite
infections.

242
Q

What does the Th2 pathway promote compared to Th1

A

tissue repair

rather than inflammation.

243
Q

When is t cell lineage decided

A

initial priming - when pathogen is first detected

244
Q

What plays a major role in t cell lineage decisions

A

Cytokines secreted by antigen-presenting

cells and other innate cells (signal 3)

245
Q

What happens to cytokines involved in t cell lineage decisions

A

recognised by receptors that activate particular STAT proteins.

The STAT proteins induce the expression of additional lineage defining transcription factors such as T-bet and GATA-3 that reprogram the cell.

246
Q

What do STAT proteins do

A

induce the expression of additional lineage defining transcription factors such as T-bet and GATA-3 that reprogram the cell.

247
Q

Can T cells produce cytokines?

A

yes - produce cytokines that act to regulate other T cell subsets

248
Q

What do Treg cells release

What does this cytokine do

A

TGF-β

maintains homeostasis by inhibiting TH1 and TH2
cell differentiation

249
Q

What do Tregs do during inflammation in the presence of IL-6

A

Tregs continue to produce TGF-β.
IL-6 can drive TH17 commitment whilst TGF-β
prevents TH1 and TH2 cells from producing IL-4 or
IFN-γ that would otherwise inhibit the TH17
response.

250
Q

What cytokine does Th1 produce

What does it do

A

IFN-γ

blocks both TH2 and
TH17 cell differentiation

251
Q

Name an IL that blocks T cell commitment for 2 subsets

A

IL-4 blocks both TH1 and TH17 cell commitment

252
Q

Discuss relation of ILCs and T cells

A

ILC1, ILC2, and ILC3 innate lymphocytes show parallels with TH1, TH2 and TH17 helper
cells respectively.

253
Q

What do ILCs respond to

A

cytokines produced by other innate cells such as DCs,

macrophages and epithelial cell

254
Q

Compare ILCs and their T cell counterpart (3)

A

share the same signature
transcription factors

often produce the same effector cytokines.

ILCs are ready to act
before the T cells.

255
Q

What do Th1 and its ILC counterpart do

what do they secrete?

A

ILC1 and TH1 cells help control infections with intracellular bacteria or viruses

IFN-γ

256
Q

What do Th2 and its ILC counterpart do

what do they secrete?

A

ILC2 and TH2 cells help deal with parasite and helminth infections

IL-5 and IL-13

257
Q

What do Th17 and its ILC counterpart do

what do they secrete?

A

ILC3 and TH17 cells deal with extracellular bacteria and fungi

IL-17 and IL-22

BoD (11 decks)

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