adaptive immunity 2

Question 1

Adaptive Immunity – Key players

two types of cell?
what kind of response?
from?
key cells?

Answer 1

B lymphocytes – Humoral response (antibody-mediated response)
From bone marrow
Antibodies (Immunoglobulins)

T lymphocytes – Cellular response (cell-mediated immune response)
From thymus
Helper T cells (CD4+)
Cytotoxic ‘Killer’ T cells (CD8+)

Question 2

T lymphocytes – Lineage and classes

lineage of T cells? what does it form?
how is CD4 and CD8 formed?
different CD4

Answer 2

Pro T (CD4- CD8-) -> AB cell (CD4+ CD8+) and Yd cell (CD4- CD8-)

AB cell (CD4+ CD+) -> CD4+ (CD4+ CD8-) and CD8+ (CD4- CD8+)

CD4+ -> TH1, TH2, TH17, Treg

Question 3

T lymphocytes - Classes

what are the 3 classes of T cells?
what do they express?
what are the main functions of these cells?

Answer 3

Helper T cells (Th)
Expresses CD4 (CD4+)
Secrete cytokines for signalling
Activate macrophage, B cells & CTL

Regulatory T cells (Treg)
Inhibit (suppress) function of other T cells
Control immune response and immune tolerance

Cytotoxic T cells (CTL)
Expresses CD8 (CD8+)
Kills virus-infected cells, cancer cells, graft cells (organ transplant therefore take immunosupressant)

Question 4

Adaptive immunity brief overview of cell mediated and humoral response

how can CTL be activated? what will happen after it is activated?

How can TH be activated? what happens once they are activated?

how do you fully activate a B cell?

Answer 4

CTL can be activated by foreign antigen on nucleated cell. Once activated, it seeks out cells presenting similar peptides, destroy cells via chemical warfare. Subset of activated CTL will differentiate into memory T cells.

T-helper cells are activated when they recognise foreign peptides presented on antigen presenting cells like monocytes, macrophages and B cells. Once they are activated, they release cytokines to signal other immune cells which will proliferate and make more clones.

To full activate a B cell, you need cytokines from T-helper cell therefore B cells present antigen to T-cell to activate it. Cytokines released and more B cells can differentiate into plasma cells + memory B cells

Question 5

Antigen recognition by B and T lymphocytes

what do they have?
what do they recognise?

Answer 5

Receptors on surface (BCR or TCR)

Recognise different structures on pathogen
Antigens from different pathogen
Different areas of same antigen

Distinguish non-self from self – autoimmune disease if fail

Question 6

BCR
B cell receptor
how do they recognise it? type of response?

Answer 6

BCR recognise antigens directly
Antibody-dependent response

Humoral immunity

Question 7

TCR
T cell receptor
how do they recognise it? type of response?

Answer 7

TCR requires cells to process and present antigenic peptides
Antibody-independent response

Cell-mediated immunity

Question 8

MHC and BCR/TCR

what response is antigen presenting immune cell part of?

Answer 8

Antigen presenting immune cell is part of the innate immune response which will present the antigenic peptides on the MHC (I or II) which will present to TCR

MHC and TCR bridge gap betweem innate + adaptive immunity

Question 9

MHC

class I present where? 
what does it do?
what is it recognised by?

class II where?
how is this presented?
recognised by?

Answer 9

MHC Class I
Present in all nucleated cells (including professional APCs)
Continuous sampling of peptides from within the cells (cytosol) -> will make sure cells are normal + healthy, in case cells are infected or cancerous
Recognised by CD8+ CTL

MHC Class II
Present on professional APCs only (e.g. mononuclear phagocytes, dendritic cells)
APCs engulf and breaks-up pathogens from outside the cell, presents broken-up peptides on MHC Class II
Recognised by CD4+ Th cells

Question 10

MHC
exemptions to the rule

what engulfed material can be presented on MHC class I? why?

when will intracellular proteins be present on MHC class II? why?

Answer 10

Extracellular peptides presented in MHC class I in cross-presentation -> this means that engulfed extracellular proteins can be presented on MHC class I to ensure not only humoral arm of adaptive immune resposne is activated but also Killer - T cells activated too

Intracellular peptides presented by MHC class II during autophagy -> cells will degrade a part of itself to get rid of misfolded protein + damaged organells which will be displayed on MHC class II

Question 11

Important structures: MHC Class I

how many chains?
sub units of aplah chain?
what makes up the peptide-binding cleft? what does this do?
where is disulfide bonds? why?
what will a3 have? why?

units of B?
why does it have a disulfide bond?
where does B2 bind? what present the peptide?

Answer 11

2 chains - a and B

alpha chain has 3 sub units
a1 and a2 will make up the peptide-binding cleft which presents the antigen peptide
disulfide bonds in 2 + 3 to stabilse protein as a chain is large
a3 will have a transmembrane region to anchor cell to cell membrane

B is 1 unit
it has disulfie bond to stabilise unit + inetgrate woth a chain (a3)
B2 and a3 arms support a1 + a2 hands that present the peptide

Question 12

Antigen processing and presentation in nucleated cells(MHC class I presentation)

what happens to proteins destine dfor degradation?
what will happen to some of them? what happens to rest?

if cells are normal, what happens? if not?

Answer 12

proteins destined for degradation are tagged by ubiquitin conjugation which tells proteosome to chop the proteins into peptides

Some a.a. broken down to be recycled but some will be traffiked into ER where it will be coded into MHC class I . trafikked via golgi body + presented on the cell where they can be recognised by CD8+ cytoxic T cells.

If cells are normal, no CTL can recognise it therefore cells carry on as usual BUT if cells are infected by virus or mutated, CTL will recognise it and kill cell

Question 13

Important structures: MHC Class II

made up of?
is it same of different a chain to MHC class I?

how many disulfide bonds? where?

what makes up the peptide binding cleft?
transmembrane region anchor?

Answer 13

made up by 2 symmetrical chains
a and B chain ( a1, a2, B1, B2)
DIFFERENT a chain to MHC class I

there are 2 domains stabilised by disulfide bonds (b has 2 and a has 1)
a1 + b1 make up the peptide binding cleft

both chains have a transmembrane region anchor

Question 14

Antigen processing and presentation in APC (MHC class II presentation)

what do apc have the ability to do? which MHC class does this correspond to?

what happens to the pathogen? what about the MHC class II?

what happens before it is presented on the surface of APC?

Answer 14

APCs have the ability to engulf pathogens therefore MHC class II

The pathogen will be uptaken, degraded and processed in endolytic vesicles in APC 
At the same time, MHC class II will be sent from ER and traffiked away from golgi apparatus to the endolytic vesicle 

The MHC class II will associate with the pathogen antigen. Now it will be trafikked and presented on surface of APC where it will be recognised by CD4+ helper T cells

Question 15

2 step recognition with TCR and MHC

what must the TCR be able to do?
what must the CD4 receptor be able to do?

Answer 15

2 step recognition phase
T cell receptor needs to fit the peptide presented on MHC class II
CD4 receptor needs to bind to appropriate partner to lock in this recognition signal

for killer T cell, it is the CD8+ and not CD4+

Question 16

TCR lineage

what does the cell lineage depend on?
what can it either differentiate into?
what do both chains have? (3)

the 3 different AB cell
whats the only YD cell?

Answer 16

T cell lineage (classes) depends on TCR glycoprotein chain
It will either differentiate into aB or Yo cells
Both chains have domains, variable + constant region

αβ (alpha beta) T cells
CD4+ or CD8+
CD4+ becomes Th cells
CD8+ becomes CTL

γδ (gamma delta) T cells
CD4- and CD8-

Question 17

αβ and γδ chains

ab
what is the TCR made up of?
where is the majority of the T cell population?
what does it require of the antigen?

yd
what is the tcr made up of?
where is the highest abundance?
why is it unconventional?
what does it recognise?

Answer 17

αβ (alpha beta) T cells
TCR made up of one α chain and one β chain
Majority of T cell population in peripheral blood
Requires antigen presentation on Major Histocompatibility Complex (MHC) – peptide antigens

γδ (gamma delta) T cells
TCR made up of one γ chain and one δ chain
Highest abundance in gut mucosa
‘Unconventional’ - Do not need MHC presentation to work
Recognise non-peptide antigen?

Question 18

Important structures: TCRs

how are yd and ab similar? what is different?
what are they stabilised by?
what do they have on the chain?
what do they have in the transmembrane region?

Answer 18

γδ TCRs similar to αβ TCRs, but different chains

chains are nearly symmetrical
stabilised by 2 disulfide bonds in each chain
has a cytoplasmic tail in the transmembrane region
has glycocarb groups on the chain

Question 19

Signals for T cell activation

how many signals needed? why?

what are the signals?

Answer 19

need 3 signals to prevent T cells activating prematurely and damaging healthy cells

signal 1 = binding of the the TCR to the peptides presented on the MHC molecules + the binding of the co-recptor CD4 or CD8 to the MHC

signal 2 = co-stimulation signal as a result of binding of receptors on the antigen presenting cell + T cell
e.g CD80/CD86 is present on cells including APC but CD28 is only present on T cells therefore can confirm identity of T cells

signal 3 = cytokines in the environment. APC secrete cytokines to activate T cells hence tell T cells what to differentiate into

Question 20

CD8/CD4 and MHC I/II

describe the two interactions

Answer 20

TCR of CD8+ cytoxic T cell interacts with assymetrical MHC class I molecule and interaction of CD8 co-receptor with the MHC

TCR of CD4+ helper T cells binds to symetrical MHC class II molecule and interaction of CD4 co-receptor with the MHC

Question 21

Cytokines in T cells

what are cytokines?
what are a major source of cytokines?

Answer 21

Cytokines – chemical messengers in immune system; cells have receptors to ‘read’ chemical messages

T cells are a major source of cytokines, especially CD4+ Th cells (co-ordinated immune respone)

Th cells can produce cytokines to respond to different types of infection

Question 22

Th cells for different types of infection

what are the different types?

describe their lineage?
what they are used for?

Answer 22

Naive CD4-T -> IL-12 -> Th1 -> IFN-y + TNF-a cell-mediated immunity (intraceullar immunity, bacteria)

Naive CD4-T -> IL-4 -> Th2 -> IL-4. IL-5, IL-13 humoral immunity (extracellular parasites)

Naive CD4-T -> IL-6 -> Th17 -> IL-17A, IL-17F, IL-22 cell-mediated inflammation, autoimmune diseases (extracellular phogens, fungi)

Naive CD4-T -> TGF-B -> Treg -> TGF-B, IL-10 immunoregulation (peripheral tolerance)

Question 23

Balancing CD4+ T cell responses

what will secreted cytokines do for the different sub classes?
how do they know which one to differentiate into? (2)

Answer 23

Cytokines secreted by different T cells will promote proliferation of that sub-class but inhibit the pro-liferation of other subclasses

So many different instrcutions hence very complex process

Cytokines released in different concentrations
Cytokines bound to MOST receptors will win

Question 24

Th1-mediated immune response
function, diseases and main cytokine

3 main functions?
main cytokines? (2)
effector?

3 Th1 mediated diseases?

Answer 24

Function
Protecting against intracellular infections by viruses and bacteria; eliminating cancerous cells
Proinflammatory responses (via cytokines)
Production of IgG for opsonisation

Main cytokine
Polarizing: IL-12
Effector: IFNγ (promote + inhibit)

Th1-mediated disease
Granulomas
MS
Some autoimmune disease (type 1 diabetes)

Question 25

Th1-mediated immune response
process

what antigen presented on after engulfed by APC? recognised by?

what happens next?
what cytokine will stimulate the T cell? to produce what?

what is the effects of this?

Answer 25

APC engulf bacteria after it invades the body and is presented on MHC class II which is recognised by CD4+ T cells

Once 3 signals have been met, cytokines (IL-12) will stimulate T cell to polarise into TH1 cell and produce IFN-y

Increased macrophage capacity via activation so can lyse and englug more bacteria and increased MHC presentation

Cell activated B cells switch to IgG which leads to tagging bacteria hence opsonisation -> phagocytosed by other immune cells like macrophages

Question 26

Phagocytosis

what signal is required to merge phagosome and lysosome?

Answer 26

Pathogens destroyed in phagolysosome
Combination of oxidative and non-oxidative process (ROS and RNS)

Merging of phagosome and lysosome requires Th1 signals

Question 27

Signals required for Th1-mediated immune response

3 things?
what does it lead to?

Answer 27

MHC - peptide interaction
co signals
IFN - y

leads to macrophage activation + killing of phagocytosed bacteria

Question 28

Outcomes of macrophage activation

increase of what enzyme prodiction? leading to?

which cytokines are released? 3 effects of this?

what 4 other things take place? what do they do?

Answer 28

Increase ROS, RNS, lysosomal enzyme production
Killing of phagocytosed pathogens

Secretion of cytokines – IFNγ, TNFα, IL-2
Promote local inflammation
Recruit neutrophils & monocytes
Promote phagocytosis

Tissue repair signals (subset of macrophage)
Platelet-derived growth factor (PDGF) for regulation of cell growth/division
TGF-β for collagen synthesis
Fibroblast growth factor (FGF) for angiogenesis

Question 29

Pathogens resistant to phagocytosis

3 examples

Answer 29

Salmonella
- Dampen inflammatory response; ‘resistant’ to ROS and RNS

Mycobacterium
- Prevents phagosome-lysosome fusion

Pathogens that cannot be killed by phagocytes (e.g. macrophages) persists in phagosome > Chronic infection

Question 30

Th2-mediated immune response

function?
how does it do this? give examples

Th2 mediated disease?

Answer 30

Function – Activate humoral responses against toxins, extracellular parasites & bacteria

Extracellular parasites (e.g. helminths): Ab tagging to recruit other cells; Release of cytotoxic chemicals by eosinophils, macrophage, neutrophils

Extracellular bacteria: Blocking by Abs

Toxins: Neutralisation by Ab binding to active sites

Th2-mediated disease
Allergies & asthma development

Question 31

Th2-mediated immune response against helminths

main polarising cytokine?
main effector cytokines? (3)

Answer 31

Main polarizing cytokine
IL-4

Main effector cytokine
IL-4 (production of IgG2, IgG4, IgE, mast cell degranulation)
IL-5 (eosinophil activation for parasites)
IL-13 (preparation of organs to expel helminths, anti-inflammatory)

Question 32

Antibody-dependent cellular cytoxicity (ADCC)

where does variable region bind?
what will happen with constant region?
effect of this?

Answer 32

variable region of antibodies bind to pathogen e.g. IgE bind to Helminth parasite

Different immune cells like eosinophil can recognise constant region

Binding of immune cell + constant region lead to release of lytic proteins to kill pathogen

Question 33

Other CD4+ T cells

2 types
describe function

Answer 33

Th17 cells
Recently discovered
Produces IL-17
Linked to IBD & arthritis

Treg cells
Maintains homeostasis and tolerance within immune system
E.g. inducible Tregs, CD25+CD45RBlo Tregs

Question 34

CD8+ Cytotoxic T cells

how is it activated?
what are the 3 killing mechanisms?

Answer 34

Activation: Recognise antigens on MHC Class I + CD8 interaction; confirmation signal CD80/CD86-CD28 ‘handshake’

3 killing mechanisms after activation

Secretion of cytokines e.g. TNF-α, IFN-γ – anti-viral and anti-tumour effects

Release of cytotoxic granules

Fas/FasL interactions

Question 35

Cytokines secreted by CTL

2 released?
effect of these two? what are they also produced by?

Answer 35

TNF-α
Orchestrate inflammatory response therefore vasodilation + contraction of endothelial cell
Also produced by macrophages and Th1 cells

IFN-γ
Activate macrophage
Stimulate neutrophils, NK cells
Also produced by Th1 cells and NK cells

Question 36

Release of cytotoxic granules by CTL

what do these also contain? where are they also found?

where are they released and why? where do they align along?

why serial killing ability?

how do the two molecules act?

Answer 36

CTL secrete cytotoxic granules containing perforin and granzymes
Molecules also found in NK cells

Granules release only in direction of target cells to avoid non-specific bystander damage of healthy cells
Align along immune synapse (MHC:TCR)

Serial killing ability
Release granules to kill one cell, then move on to new target and kill again

Perforin
Punches holes in the membrane of target cell
Holes allow granzymes to enter infected or cancerous cells

Granzyme
Serine proteases
Cleave proteins inside the cell, ultimately resulting in apoptosis of target cells

Question 37

Fas-mediated apoptosis

how is this process induced?

function? what become more sensitive to this? useful why?

Answer 37

Induced by binding of Fas to Fas ligand

Another mechanism to induce apoptosis of virus-infected or cancerous cells

Regulation of immune system
T cells become more and more sensitive to Fas-mediated apoptosis the longer they are activated (hence can get rid of old T cells to present excess immune response)
Prevent excessive immune response, eliminate autoreactive T-cells