L13: Adaptive immune response: Effector phase Flashcards
Which area of the lymphoid tissue do you find CD4+/ CD8+ T cells? Where do you find B cells?
CD4+/CD8+ T cells–> parafollicular cortex
B cells–> lymphoid follicle
Where a B and T lymphocytes produced and where do they mature?
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
What is it important that the B and T cells accumulate in the lymphoid tissue?
Maximum interaction can happen in these tissues
What is lymphadenopathy?
Swelling of the lymph nodes
Occurs when B and T cells are activated by antigen
Cervical, axillary and groin
How are antigens recognised by T lymphocytes?
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
How much diversity is there in the TCR?
Combinational diversity–> 10^16
Limiting factor is the number of MHC molecules
Which cells recognise which class of MHC molecules?
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
What role does costimulation play in the activation of T lymphocytes?
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
Once activated what do the naive CD4+ T cells become?
Depends on cytokine release IL-12 --> TH1 IL-4 --> TH2 IL-1 or IL-6--> TH17 IL-10 or TGFβ --> THreg
What is the best form of T cell for a cell mediated immunity? Why?
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+)
What is the best for of T cell for a humoral immunity? Why?
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
What is TH17 important for?
IL1/ IL6
Humoral immunity–> bacterial and fungal infection and autoimmune problems (unsure how)
Activated:
Neurtophils–> recruitment and activation
What are the cells responsible for regulation of the immune response?
T reg cells IL10/ TGFβ Activated: Tolerance (unresponsiveness?) Immune suppression
What are the effector function of the CD8+ cells?
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)
How does the cytoxic T cells (CD8+) kill the infected APCs?
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
How do B cells recognise antigen?
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
How many different types of B cell receptors are there?
Combinatorial diversity –> 10^11
What is different about BCR compared to TCR?
Can recognise whole microbe
Do not need APCs
How are B cells activated?
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
Label the different parts of the antibody?
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
What antibodies are produced first?
IgM
Independent of T helper cell
Thymus independent antigens
What antibodies are produced second?
IgG, IgA and IgE Depedent on T helper cell Thymus dependent antigens Isotype switch - Cytokines - CD40 activation
What happens after prolonged or repeated exposure to antigen?
Maturation of antibodies
Increased binding affinity
Upon re-challenge what cells are produced?
B memory cells
Faster, stronger and longer antibody response
How do vaccinations work?
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…
What are the function of IgG?
Effector T cell--> IFNgamma Fc-dependent phagocytosis Complement activation Neonatal immunity--> 3rd trimester, placenta transfer IgG antibodies from mother to baby Toxin/virus neutralisation
What is the function of IgE?
Effector T cells–> IL-4
Immunity against helminths
Mast cell degranulation (allergies)
What is the function of IgA?
TGFbeta
Mucosal immunity
Breast milk–> transfer antibodies
What is the function of IgM?
Thymus independent Complement activation 1st produced Massive activator of complement Control infection whilst adaptive immunity kicks in
What information is clinically useful to determine infection? Why?
- Portal of entry
- Fever, acute phase reactants (CRP), neutrophil number, phagocyte function –> treatment continue to measure to determine response, neutrophilia
- Lymphodenopathy–> show increased production of lymphocytes- mostly B cells, shows site of infection
- Measure lymphocyte number and function–> expect number to go up
Serology–> look at levels of IgM and IgG
What are the biggest medical achievements because of the study of adaptive immunity?
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
