L13: Adaptive immune response: Effector phase

Question 1

Which area of the lymphoid tissue do you find CD4+/ CD8+ T cells? Where do you find B cells?

Answer 1

CD4+/CD8+ T cells–> parafollicular cortex

B cells–> lymphoid follicle

Question 2

Where a B and T lymphocytes produced and where do they mature?

Answer 2

Both produced in bone marrow
T cells mature in thymus –> self selection –>
B cells mature following contact with antigen
More T cells in the blood than B cells

Question 3

What is it important that the B and T cells accumulate in the lymphoid tissue?

Answer 3

Maximum interaction can happen in these tissues

Question 4

What is lymphadenopathy?

Answer 4

Swelling of the lymph nodes
Occurs when B and T cells are activated by antigen
Cervical, axillary and groin

Question 5

How are antigens recognised by T lymphocytes?

Answer 5

T cell receptor (TCR) recognises MHC associated peptide
Class I–> 9aa peptide
Class II–> 20/30aa peptide
The variable subunit consists of α and β chains–> recognise the peptide, accommodate an array of different peptides
Constant region–> doesn’t change
Part of bigger complex
–> CD3 complex (all T cells) ( signal transduction)
–> Accessory molecule CD4 or CD8

Question 6

How much diversity is there in the TCR?

Answer 6

Combinational diversity–> 10^16

Limiting factor is the number of MHC molecules

Question 7

Which cells recognise which class of MHC molecules?

Answer 7

Helper T cells (CD4+) –> peptide presented by MHC II
Cytotoxic T cells (CD8+) –> peptide presented by MHC I

Remember 1 x 8= 8 so CD8 is MHC I
2 x 4= 8 so CD4 is MHC II

Question 8

What role does costimulation play in the activation of T lymphocytes?

Answer 8

APC travels to lymph node–> T cell zone (parafollicular cortex)
MHC I (CD8+) or MHC II (CD4+) activated
APC also has costimulatory protein B7 (upregulated when activated)
Binds to CD28 (structure) on T cell to activate the T cell
APC also release cytokines which determine form of T helper cell the T cell becomes

Question 9

Once activated what do the naive CD4+ T cells become?

Answer 9

Depends on cytokine release
IL-12 --> TH1
IL-4 --> TH2
IL-1 or IL-6--> TH17
IL-10 or TGFβ --> THreg

Question 10

What is the best form of T cell for a cell mediated immunity? Why?

Answer 10

Intracellular* and extracellular pathogens
TH1 (IL-12)
Activates:
CD8+ differentiation into cytotoxic T cells
Macrophage recruitment and activation
B cells produce IgG or IgA

(*intracellular can activate both CD4+and CD8+)

Question 11

What is the best for of T cell for a humoral immunity? Why?

Answer 11

Extracellular--> Humoral Immunity
(parasites and worms)
TH2 (IL-4)
Activates:
B cells --> IgE production --> only one that can activated eosinophils and mast cells 
Eosinophils --> Killing of pathogens 
Mast cells --> Allergies

Question 12

What is TH17 important for?

Answer 12

IL1/ IL6
Humoral immunity–> bacterial and fungal infection and autoimmune problems (unsure how)
Activated:
Neurtophils–> recruitment and activation

Question 13

What are the cells responsible for regulation of the immune response?

Answer 13

T reg cells 
IL10/ TGFβ
Activated:
Tolerance (unresponsiveness?)
Immune suppression

Question 14

What are the effector function of the CD8+ cells?

Answer 14

Intracellular microbes activate MHC I which activate naive CD8+ cells
Naive CD8+ –> Effector T cells and Memory CD8+ T cells
However they also activate MHC I–> CD4+ cells –> TH1 cells (IL-12) as they are needed to convert Effector T cells –> Cytotoxic T cells (release cytokines which result in conversion)

Question 15

How does the cytoxic T cells (CD8+) kill the infected APCs?

Answer 15

Bind to MHC I associated peptide
Release cytokine
Also 2 enzymes produced intracellularly
–> Perforin–> forms perforin pore in infected cell
–> Granzyme–> enters through pore–> apoptosis

Question 16

How do B cells recognise antigen?

Answer 16

B cell receptor (BCR)–> membrane bound antibody
Unique specificity for each cell
Variable–> accommodate different antigens
Constant region
Signal transduction Ig alpha and Ig beta next to BCR

Question 17

How many different types of B cell receptors are there?

Answer 17

Combinatorial diversity –> 10^11

Question 18

What is different about BCR compared to TCR?

Answer 18

Can recognise whole microbe

Do not need APCs

Question 19

How are B cells activated?

Answer 19

Antigen activates two B cells receptors
1st signal–> BCR engagement (two BCR inteact)
–> signal transduction (Ig alpha and Ig beta in membrane)
–> Antigen processing and presentation–>Antigen taken into endosome and processed
–> Increased B7 protein (costimulator) –> becomes an APC–> Microbial peptide presented in MHC II (except virus–> presented MHC I and killed)
2nd signal–> TCR engagement
–> antigen specific
–> Role of B7 costimulator –> fully activated T cell
3rd signal–> B cells produce IgM- T helper cell independent
–> Isotype switch- require T helper cell–> different antibodies produced
–> Require CD40 ligands (CD40L) on T helper cell
–> Bind to CD40 receptor on B cell
–> Proliferation and differentiation–> isotype switch IgM- IgG
–> Antibody production
–> Heavy chain class switching

Question 20

Label the different parts of the antibody?

Answer 20

Slide 13
1- Fab region (variable region contains antigen binding region)
2- Fc region (binds to receptors on immune cell)
3- Light chain
4- Heavy chain (determines isotype)
5- Antigen binding region
6- Hinge regions

Question 21

What antibodies are produced first?

Answer 21

IgM
Independent of T helper cell
Thymus independent antigens

Question 22

What antibodies are produced second?

Answer 22

IgG, IgA and IgE
Depedent on T helper cell
Thymus dependent antigens 
Isotype switch
- Cytokines
- CD40 activation

Question 23

What happens after prolonged or repeated exposure to antigen?

Answer 23

Maturation of antibodies

Increased binding affinity

Question 24

Upon re-challenge what cells are produced?

Answer 24

B memory cells

Faster, stronger and longer antibody response

Question 25

How do vaccinations work?

Answer 25

Give inert dose of pathogen
1st vaccination–> IgM produced, relatively low levels but clear the pathogen
2nd vaccination–> IgG produced–> increased level
–> faster, stronger, longer duration, higher affinity, isotope switch
3rd exposure–> even faster…

Question 26

What are the function of IgG?

Answer 26

Effector T cell--> IFNgamma
Fc-dependent phagocytosis 
Complement activation 
Neonatal immunity--> 3rd trimester, placenta transfer IgG antibodies from mother to baby
Toxin/virus neutralisation

Question 27

What is the function of IgE?

Answer 27

Effector T cells–> IL-4
Immunity against helminths
Mast cell degranulation (allergies)

Question 28

What is the function of IgA?

Answer 28

TGFbeta
Mucosal immunity
Breast milk–> transfer antibodies

Question 29

What is the function of IgM?

Answer 29

Thymus independent
Complement activation 
1st produced
Massive activator of complement 
Control infection whilst adaptive immunity kicks in

Question 30

What information is clinically useful to determine infection? Why?

Answer 30

1. Portal of entry
2. Fever, acute phase reactants (CRP), neutrophil number, phagocyte function –> treatment continue to measure to determine response, neutrophilia
3. Lymphodenopathy–> show increased production of lymphocytes- mostly B cells, shows site of infection
4. Measure lymphocyte number and function–> expect number to go up
   Serology–> look at levels of IgM and IgG

Question 31

What are the biggest medical achievements because of the study of adaptive immunity?

Answer 31

Disease prevention--> vaccination 
Immunoglobulin therapies--> immune deficiencies 
Immediate protection--> passive immunisation (transfer antibodies against pathogen)
Diagnostic test (antibody based)--> infectious disease, autoimmune diseases, blood type and HLA type