Adaptive Immune System Flashcards
(257 cards)
1
Q
what are different agents of pathogens
A
viruses, bacteria, fungi and parasites (protozoa and helminths)
2
Q
What is a BCR
A
B cell receptor - the surface receptor of a B lymphocyte
3
Q
What do BCRs recgonise importantly
A
molecules in their natural conformation
4
Q
where are BCRs generated
A
Bone marrow
5
Q
what happens once BCRs are activated
A
the clones differentiate into plasma cells which secrete antibody or immunoglobulin
6
Q
what is immunoglobulin
A
a soluble version of the BCR
7
Q
define antigen
What do they interact with
A
anything that can bind to an Ab
epitopes - small parts of molecules
8
Q
what are linear epitopes
A
When antibodies recognise
consecutive amino acids within a protein or peptide
9
Q
will conformational epitopes always be apparent
A
they may only appear in the molecules native 3D form
10
Q
describe the variable and constant regions of an antibody (briefly)
A
variable: N terminal - interacts a with antigen
constant: recruits effector function
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.
12
Q
What are the 3 ways that a antibody works
A
neutralisation
opsonization
complement activation
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.
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
15
Q
Where are T cells generated
A
generated in the bone marrow but mature in the thymus
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.
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
18
Q
what does MHC stand for
A
major histocompatability complex
19
Q
what does antigen processing do
A
generates the peptides for display by antigen
presenting cells
20
Q
What are the 2 classes of T cell
A
class I restricted and class II restricted
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
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)
23
Q
Name some APCs
A
dendritic cells, macrophages and B cells
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
25
What are lymphocytes derived from ?
hematopoietic stem cells via a common lymphoid progenitor
26
What are naive cells
Why are they called this
T and B cells with successfully
rearranged receptors
they have not yet been exposed to their particular antigen and been activated
27
What do lymphocytes do in primary lymphoid organs
rearrange their receptors
28
What role do naive lymphocytes take on once released from the primary lymphoid organs
patrol and respond
29
How many lymphocytes pass through a lymph node each day
2.5x10^10
30
What % of the lymphocyte pool is recirculated each hour
1-2%
31
What are the lymph nodes and spleen designed to do
optimise interaction between APC and lymphocytes
32
Describe the course of lymphatic fluid
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
33
Why is the spleen different from lymph nodes
no direct connections to the lymphatic system
34
What does the spleen do
collects antigen from the blood and deals with immune responses to blood-borne pathogens
35
How do lymphocytes enter lymph nodes from the blood
through specialised endothelia (high
| endothelial venules)
36
What do dendritic cells when they arrive at the lymph node from the periphery
enter the T cell area and present the antigen they have captured on MHC
37
Where do some B cells congregate
in B cell areas around follicular dendritic cells
38
How do FDCs trap antigens
What happens once the antigen is trapped?
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
39
What does localisation of
| APCs, B cells and T cells in the lymph node do
maximises the chance of successful B-T cell cooperation.
40
Do all B cells produce antibodies?
only produced by B cells that differentiate into plasma cells
41
Are Ab always bound to cells
They may be free in plasma, bound to cells by specific (Fc) receptors, or present in secretions such as milk, mucus and sweat
42
What does the constant domain of the Ab do
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
43
How are the heavy and light chains of antibodies held together
by covalent (disulphide bridges) and non-covalent forces
44
What are both heavy and light chains of Ab constructed of
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.
45
How can the main classes of Ig be distinguished
by their heavy chains denoted the Greek version of their Ig letter
46
Which part determines the function of the Ig
heavy chain
47
What gives the Ab flexibility
hinge region
| V-C junction
48
What is the VC junction often compared to
a ball and socket joint
49
What is the antigen binding site formed by
how is variation concentrated
interaction between heavy and light chain variable
domains
three complementarity determining
regions or CDRs
50
Which is the most variable CDR
CDR3
51
How do CDRs appear
as 3 loops at the surface, forming a variable surface for interaction with the antigen
52
What part of the loops of the CDRs do antigens bind to
Antigens can bind in tight pockets, grooves or on extended surfaces which form the antigen
binding site of the molecule.
53
How many different antibody specificities do humans have?
10^11
54
What is the first stage of diversity generation in Ab
What is this
somatic recombination
gene rearrangement in B cell development
55
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
38-46
variation in CDR1 and 2
D: 23
J: 6
56
What generates variation in CDR3
rearrangements of VDJ segments
57
How are heavy chains arranged
1st: D->J
2nd: V-->DJ
58
What is allelic exclusion
Heavy chain rearrangement can occur on both chromosomes but if a functional heavy chain is
generated then rearrangement on the other chromosome is prevented
59
How many heavy chains can a single B cell express
only 1
60
How many diversity segments do light chains have
None
61
Light chains have no diversity segments. How do they recombine to generate diversity
rearrange kappa chain first then if unproductive rearrange delta chain
62
What enzymes are involved in somatic recombination
RAG1 and 2
63
What sequences are conserved in rearrangement during diversity generation in b cells
conserved heptamer, nonamer and spacer sequences located adjacent to
V, D and J segments.
64
What are the 4 main processes to generate Ab diversity
1. Different heavy and light chain combinations
2. Selection of different heavy V, D and J segments.
3. junctional diversity
4. somatic hypermutation
65
What is junctional diversity
Variable addition and loss of nucleotides at VDJ junctions
66
What order does junctional diversity occur in
Addition by TdT (to N terminal)
Addition due to the recombination mechanism (P-nucleotide addition).
Deletion of nucleotides
67
What is TdT
terminal deoxynucleotidyl transferase
| enzyme that performs N-nucleotide addition in junctional diversity
68
What is somatic hypermutation
```
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
```
69
What is AID used in
deamination of cytosine to uracil in somatic hypermutation
70
What happens to Ab with increased affinity after hypermutation
selected for by affinity maturation
71
What is the mutation rate of somatic hypermutation
1 per 1000 base pairs
| per cell division.
72
What do T helper cells do generally?
s activate the B cells to produce antibody,
| generally of relatively low affinity (IgM)
73
What is one model for the interaction between B cells and T follicular helper cells?
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
74
mature B cells usually present which Ig isotypes?
How are these generated?
Can they change their isotype?
IgM and IgD
IgM and IgD are coexpressed and are generated by alternative splicing
yes via class/isotype switching
75
What choice determines whether an Ig will be soluble or membrane bound while still having the same VDJ specificity?
different poly-A sites
76
What are the 5 human Ig isotypes?
IgM, IgG, IgA, IgD and IgE,
77
Which Ig isotypes are split into subclasses?
What are the subclasses?
IgG and IgA
IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2
78
What determines most of the the effector function of an antibody?
Fc receptors
79
What do Fc receptors do
deliver the antibody to different anatomical
| sites and link antigen to molecules or cells that effect its destruction.
80
What controls recruitment of effector cells
Differential expression
| of Fc receptors by the effector cells
81
What are 2 key differences between Fc receptors
affinity
| valency
82
How do affinity and valency affect Fc receptors
some are of high affinity and bind monovalent
| antibody/antigen complexes while others are low affinity receptors and only bind multivalent antibody/antigen complexes.
83
What is the Kd of a high and low affinity Fc receptor
high: 10^-9
low: 10^-6
84
Give 2 monovalent Fc receptors
Fc (gamma)RII and III
85
Give 1 multivalent fc receptor
Fc (gamma) RI
86
What do the differences in affinity and valency provide for different Fc receptors
different levels of sensitivity to cells expressing the different receptors.
87
What do macrophages and neutrophils express to aid opsonisation
Fcg receptors which efficiently
recognise the Fc region of IgG antibodies,
particularly IgG1
88
What happens when the Fc gamma receptors on macrophages and neutrophils interact with antibodies?
leads to
phagocyte activation and results in enhanced
antigen uptake and degradation
89
Which Ig activates complement very effectively?
Name a receptor that recognises it efficiently?
IgM
the C3b receptor
90
What is the purpose of binding of antigen/antibody
complexes by C3b receptors present on red blood
cells
allows delivery of the complex to the liver and spleen for removal by macrophages
91
What is ADCC
Antibody dependent cell mediated cytotoxicity
92
Name 3 cells which express Fc (gamma) RIII
Natural killer cells,
neutrophils,
eosinophils
(also phagocytes)
93
What does Fc (gamma) RIII recognise?
it is a low affinity receptor that recognises only Ab/antigen complexes
94
What does ligation of the Fc (gamma) RIII on NK cells do
triggers release of cytoplasmic granules
| containing lytic enzymes.
95
Can free Ig trigger ADCC
no - requires complexes of
antibody and antigen to provide multiple Fc
regions for recognition.
96
Which granulocyte mediates a unique type of ADCC?
Describe
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.
97
What receptors do mast cells and basophils express and what do they recognise
FceRI and FcgRIII for IgE and IgG.
98
Why do mast cells and basophils have 2 types of Fc receptor
When is a similar response also elicited
Crosslinking of these receptors signals
release of inflammatory mediators into
surrounding tissues.
during allergic reactions
when allergens bind to IgE on mast cells
99
How long does degranulation of basophils and mast cells take?
What is released?
seconds
vasoactive amines such as
histamine and lipid and cytokine mediators
of inflammation such as, prostaglandins,
leukotrienes and TNF-a
100
Which 2 Ig protect mucosal surfaces from infection
IgA and to a lesser extent IgM
101
How does IgA cross the epithelial layer on mucosal surfaces?
A receptor for
polymeric Ig recognises the J chain region of IgA
and transports it across the epithelial cell.
102
Which Ig is important in milk for infants
IgA (this is the enzyme that crosses mucosal surfaces)
103
What do antibodies do in the gut of infants
IgA from breast milk remains in the gut and prevents
| attachment of bacteria and toxins to gut epithelia.
104
Which antibody is important for fetal protection?
IgG
105
How does IgG cross from the mother to the fetus?
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
How do ruminants (NOT humans) acquire IgG
postnatally from colostrum via an IgG-specific
| receptor in the gut
107
How do B cells shut down Ab responses?
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
Which Fc is important in terminating an Ab immune response?
Fc(gamma)RIIB
109
How do Fc(gamma) RIIB receptors help control inflammatory responses?
by antagonising the activity of activatory Fc receptors
110
Which cells express FcgRIIB
many including macrophages, neutrophils, eosinophils and mast cells.
111
What does the affinity of the Ab refer to ?
e interaction between a single antibody binding site
| and a single monovalent epitope on an antigen
112
How many antigen binding sites does an Ab have
What do they do with these sites?
at least 2
often bind to two epitopes on the same antigen
113
What is avidity
a measure of the strength
| of interaction due to recognition of polyvalent epitopes
114
Describe the affinity and avidity of IgM
low
| affinity but bind with high avidity
115
What is the Major Histocompatibility complex (MHC)?
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
What are MHC class I and II molecules?
cell surface glycoproteins whose function is to present
| peptides to T cells
117
Give an overview of the structure of MHC class I molecules
made from a transmembrane heavy or alpha
| chain, which is non-covalently linked to b2-microglobulin.
118
Describe the heavy chain of the MHC class I molecule
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
What can the peptide binding groove of the heavy chain of MHC class I molecules accomodate?
peptides that are often 8-9 amino
| acids in length
120
What is the size of the heavy chain and the beta2 microglobulin in MHC Class I molecules?
heavy chain: 45kDa
beta2 microglobulin: 12kDa
121
How does the structure of MHC class II relate to class I molecules?
```
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
True or false:
Antibodies and T cell receptors show great binding specificity
How does this compare to MHC molecules?
True
A single MHC molecule in
contrast is able to bind a broad range of peptides composed of different amino acid
combinations
123
What do the pockets in an MHC class I binding groove do?
What is the point?
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
Can peptides longer than 8-9 amino acids fit into the binding groove in MHC Class I molecules
yes if bent in the middle
125
How does the MHC class II binding groove differ from that of the class I ?
```
The class II peptide groove is open ended and can
bind longer peptides 13-25 amino acids, in an extended conformation.
```
126
Generally, what is MHC diversity due to
polygeny and polymorphism
127
What are MHC molecules also known as?
Human Leukocyte Antigens (HLA)
128
What is polygeny in MHC diversity?
```
the expression of multiple independent loci encoding class I and class II
genes
```
129
What are the different isotype of each class of MHC molecule?
3 of each
class I :HLA-A, HLA-B and HLA-C
```
class II: HLA-DP,
HLA-DQ and HLA-DR
```
130
What are the most polymorphic genes known
MHC genes
131
How many Class I MHC alleles are there?
How many proteins does this refer to?
13,680 Class I alleles corresponding to 9,341
| protein variants
132
By how many amino acids can MHC alleles differ by?
between 1 and 50
133
MHC genes are the most polymorphic genes known. Is this normal
This extensive allelic polymorphism is
| thought to be pathogen driven and is unique to the MHC.
134
Describe MHC inheritance
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
What does it mean to say MHC alleles are co-dominantly expressed
t both maternal and
| paternal haplotypes are expressed together on the same cell
136
How common is it to be homozygous for MHC alleles
In outbred populations
polymorphism at each loci makes it virtually impossible for two individuals to express the same
combination of MHC alleles
137
Why is it better to be heterozygous for MHC alleles
Heterozygotes can present more peptides and activate more T cells than homozygotes.
138
Where is polymorphism concentrated in MHC molecules
in the peptide binding domain and the domain that interacts with the TCR
139
What will the TCR see of the MHC
a combination of a
| particular MHC molecule associated with a particular peptide (MHC restriction)
140
Can a TCR respond to the same peptide presented by different MHC molecules
this is very unusual due to MHC restriction
141
What are anchor residues (MHC)
conserved amino acids at a certain position of a peptide
they anchor the peptide to the binding groove
142
What do anchor residues determine
the peptide binding motif of a particular MHC
143
Why can a single MHC molecule present a range of peptides?
Amino acids at non-anchor positions are not under the same strict constraints and may vary
considerably
144
What are MHC molecules occupied by in the absence of infection?
self peptides
145
Why does peptide presentation require a balance in binding characteristics? (2)
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
Typically a cell with 100,000 MHC class I molecules of a single allotype presents how many different peptides?
1000
147
What fraction of random peptides are able to bind a particular MHC allele?
Roughly 1/1,000-1/10,000
148
An individual peptide-MHC complex can present how many molecules per cell?
What is the mean/
roughly 1-5,000 molecules per
cell
mean=100
149
What is the range of MHC-peptide complexes that can activate a T Cell
from a single complex up to a few thousand
150
Describe the genetic associations of MHCs with autoimmune diseases and with infectious diseases
many strong genetic associations with autoimmune disease but
| associations with infectious disease are much weaker
151
Why do we use chickens to explore the development of MHC molecules?
they have a single dominantly expressed MHC class I molecule
152
Compare promiscuous and fastidious MHC class I molecules in chickens
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
What happens to promiscuous and fastidious chicken MCHI alleles after infection
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
Why would fastidious chicken MHCI haplotypes be reduced after MDV infection?
they were unable to find viral peptides to
| present
155
How have MHC moleules developed to counter both intra and extra cellular infections?
```
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
What are MHC CI molecules designed to do?
present peptides from within the cell to CD8 cytotoxic T
| cells
157
What primarily degrades proteins within the cytosol
What happens to the products?
proteasome
moved to ER via TAP
158
How are peptides from the proteasome moved to the ER
What happens to the peptides in the ER
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
What happens to fully loaded MHC peptide complexes in the ER
they are released from the chaperones, pass through the golgi, and follow
the secretory pathway to the cell surface.
160
How can the Peptide Loading complex (PLC) be visualised practically/
by single-particle electron cryo-microscopy
161
Describe the MHC Class I antigen processing pathway
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
True or false
| MHC Class I molecules have to pass through the ER during biosynthesis
False
MHC class II (NOT 1) molecules have to pass through the ER during their
biosynthesis.
163
What prevents MHC CII binding to peptides as it passes through the ER
a/b chains associate with a third
| component invariant chain (Ii)
164
Give the 3 actions of the invariant chain of the MHC CII molecule as it passes through the ER
a) blocks the peptide binding groove
b) acts as a folding chaperone
c) targets class II/Ii complexes into the endocytic pathway.
165
Where do the MHC CII molecules pass after the ER
Golgi to be sorted un to the endocytic pathway
166
What happens to MHC CII in the endocytic pathway
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
What helps loading of appropriate antigen derived peptides onto MHC CII in the endocytic pathway
the class II related molecule HLA-DM.
168
What is the path of the MCH CII molecule after it has been loaded in the MIIC compartment during the endocytic pathway?
```
MHC class II/peptide complexes are transported to the cell surface for presentation to CD4
T cells, but the pathway used is unknown
```
169
Does the MHC locus only have Class I and II genes
```
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
What are the 7 genes included in the MHC that are not the classical Class I and II genes
HLA-DM
HLA-DO
2 LMP components of the proteasome
TAP1 and 2 and TAPBP
171
What are HLA-DM and -DO involved in?
regulating peptide presentation by MHC class II molecules.
172
What is TAPBP
```
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
The genes for TAP1, TAP2, and TAPBP are located near which MHC class region?
Expand
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
Are T cells important in humoural or cell mediated adaptive immunity?
both
175
How are the main 2 subsets of t cells distinguished?
d by
expression of different co-receptor molecules CD4 and CD8, their effector function and MHC
restriction
176
What is the TCR encoded by
wo polypeptide chains each containing a constant and a
| variable region
177
What are individual domains of a TCR related to in the Ig?
the Ig fold domain
178
What is the immunoglobulin superfamily?
Molecules containing Ig like domains are members of the immunoglobulin superfamily.
179
Give the 4 key ways TCRs differ from BCRs
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
What are the stages of TCR rearrangement
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
describe germline reshuffling in TCR diversity generation
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
What are the enzymes stimulated to reshuffle TCR DNA? What molecule stimulates them?
RAG1/2 stimulated by thymosin etc in thymus to shuffle DNA
183
What happens in the beta chain reshuffle stage of TCR diversity generation
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
What happens with non template nucleotides in TCR diversity generation?
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
Are RAG1 and 2 used in BCR diversity?
Yes used in both TCR and BCR diversity generation
186
After rearrangement of the TCR DNA what will the exons now code for
a leader sequence, a VDJ region, a constant region
| and a transmembrane region
187
What is the most variable region of the TCR
What does it do
Where is it focussed?
CDR3
CDR3 makes
the major contact with peptide present in the
MHC groove.
VDJ junction
188
What are the 3 things T Cells are selected for?
1) successful β chain rearrangement
2) positive selection
3) negative selection
189
What is the aim of T cell selection
to "eliminate the harmful and reject the useless".
190
What % of double positive T cells survive
2%
191
What does negative selection of T cells do
prevent autoimmunity by deleting autoreactive cells
192
What does positive selection of T cells do
ensures that peripheral
| T cells will be useful since cells that cannot recognise self MHC cannot become activated.
193
Do B Cells undergo positive selection
no
| Positive selection is unique to T cells.
194
How does positive selection of T cells work (3 stages)
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
What happens to thymocytes
expressing TCRs with a "high" affinity for
MHC/self peptide
eliminated from the
| repertoire by apoptosis
196
Which T cells are not affected by negative selection
Negative selection can not
eliminate T cells with receptors recognising
MHC/peptide combinations that are not
expressed in the thymus
197
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?
by mechanisms that operate in the periphery
198
How do T cell precursors progress through the thymus?
bone marrow precursors
enter the outer sub-capsular region and progress towards the medulla
through the cortex.
199
What cells mediate positive selection of T cells in the thymus
Where are they found
cortical epithelial cells
cortex of the thymus
200
Describe the cortex of the thymus
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
What is the major cause of thymocyte death?
lack of positive selection
202
Name 3 cell types present in the medulla of the thymus
Medullary epithelial cells
bone marrow derived dendritic cells
macrophages
203
Which cells are most efficient at triggering negative selection in T cells
Bone marrow derived cells (dendritic cells and
| macrophages)
204
What are macrophages important for in the medulla of the thymus
removing thymocytes that fail to mature
205
What happens to t cells that survive selection in the thymus
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
Can mature naive t cells recognise MHC/peptide complexes?
yes
Mature naïve T cells have TCRs capable of recognising MHC/peptide complexes but require
additional stimulation to become activated
207
What is the 2 signal hypothesis
signal 1 is
| delivered by TCR engagement and co-stimulatory molecules deliver signal 2
208
What does CD28 do
molecule on t cell which interacts with molecules on the APC
delivers co-stimulation to t cell needed for t cell activation
209
What is CD40L
a molecule on the t cell that would interact with CD40 on the APC
210
What is a defining feature of professional APCs?
Expression of costimulatory molecules
211
name 3 professional APCs
DCs,
| Macrophages and activated B cells
212
Where are dendritic cells found
What do they do
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
What do DCs do once they have their antigen cargo?
migrate to draining lymph nodes where they remain and present antigen to
circulating T cell
214
How do naive t cells enter the lymphoid organs?
through specialised endothelial cells
| high endothelial venules
215
Do naive t cells remain in a lymph node once they reach one?
no
They continually circulate through lymph nodes and back to the
blood, making contact with thousands of APCs every day
216
What induces a naive T cell to proliferate
What do they proliferate and differentiate into ?
Binding of
MHC II:peptide complexes by the TCR and CD28 by B7
an expanded population of armed effector T helper cells.
217
How does a B cell become fully active?
must interact with armed effector T helper cells
218
Describe the interaction between b cell and helper t cell
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
Is Interaction between B cell and T cell co-stimulatory molecules important
yes
| it is essential and leads to mutual activation (B-T cell co-operation).
220
What are the co stimulatory elements expressed on b and t cells ?
Which binds to which?
T: CD28/CD40L
B:B7/CD40
CD28-B7
CD40L-CD40
221
What is the 3rd cell-cell interaction of the primary antibody response
the binding of activated B cells to follicular dendritic
| cells
222
What are FDCs (3)
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
What has the intrinsic ability to stimulate naïve B cells without the need for
B cell/T cell interaction
thymus independent
| antigens (TI antigens)
224
What are TI antigens typically?
microbial products composed of repetitive
elements (polysaccharides and lipopolysaccharides) which cross-link membrane Ig and induce
B cell proliferation.
225
What are CD8 T cells destined to become?
What about CD4 t cells?
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
What do Th1 cells do
produce cytokines that support inflammation and cell mediated responses
227
What is the signature TF of Th1 cells
T-BET
228
What infections are Th1 cells important for
```
intracellular pathogens (e.g.
mycobacteria).
```
229
What cells do Th1 cells mainly activate?
macrophages,
| NK cells and CTLs
230
What do Th2 cells do
activate immune responses that assist in the elimination of
| parasitic infections.
231
What is the transcription factor for Th2
GATA3
232
What are Th17 cells involved in
transcription factor?
defence against extracellular bacteria and fungi
RORγT
233
What are Tfh cells?
Follicular helper T cells
essential promoting antibody responses
234
What is the TF for Follicular helper T cells
BCL-6
235
What are Tregs
T cell suppressors -suppress the activity of other T cells
236
Transcription factor for Tregs
FOXP3
237
When does the differentiation into Th1 or 2 subsets occur?
Why is this important to note
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
Does amount of antigen affect immune response?
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
Why is it important to get Th1/2 decisions right early
bias towards one or the other becomes self reinforcing
240
Which t cell pathway leads to cell mediated immunity
What does it do
The TH1 pathway
It
increases inflammation to defend against
intracellular bacterial, viral and protozoan infections
241
What does the Th2 pathway do
humoral immunity
promotes production of pathogenspecific IgE antibodies that work with basophils,
mast cells and eosinophils to control parasite
infections.
242
What does the Th2 pathway promote compared to Th1
tissue repair
| rather than inflammation.
243
When is t cell lineage decided
initial priming - when pathogen is first detected
244
What plays a major role in t cell lineage decisions
Cytokines secreted by antigen-presenting
| cells and other innate cells (signal 3)
245
What happens to cytokines involved in t cell lineage decisions
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
What do STAT proteins do
induce the expression of additional lineage defining transcription factors such as T-bet and GATA-3 that reprogram the cell.
247
Can T cells produce cytokines?
yes - produce cytokines that act to regulate other T cell subsets
248
What do Treg cells release
What does this cytokine do
TGF-β
maintains homeostasis by inhibiting TH1 and TH2
cell differentiation
249
What do Tregs do during inflammation in the presence of IL-6
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
What cytokine does Th1 produce
What does it do
IFN-γ
blocks both TH2 and
TH17 cell differentiation
251
Name an IL that blocks T cell commitment for 2 subsets
IL-4 blocks both TH1 and TH17 cell commitment
252
Discuss relation of ILCs and T cells
ILC1, ILC2, and ILC3 innate lymphocytes show parallels with TH1, TH2 and TH17 helper
cells respectively.
253
What do ILCs respond to
cytokines produced by other innate cells such as DCs,
| macrophages and epithelial cell
254
Compare ILCs and their T cell counterpart (3)
share the same signature
transcription factors
often produce the same effector cytokines.
ILCs are ready to act
before the T cells.
255
What do Th1 and its ILC counterpart do
what do they secrete?
ILC1 and TH1 cells help control infections with intracellular bacteria or viruses
IFN-γ
256
What do Th2 and its ILC counterpart do
what do they secrete?
ILC2 and TH2 cells help deal with parasite and helminth infections
IL-5 and IL-13
257
What do Th17 and its ILC counterpart do
what do they secrete?
ILC3 and TH17 cells deal with extracellular bacteria and fungi
IL-17 and IL-22
