Sensing Microorganisms - Linking Innate and Adaptive Immunity

Question 1

Difference between MHC Class I and II?

Answer 1

Class I:
Present intracellular Ag
On all nucleated cells
Presents 7-11 AA peptides, ends of groove are closed so restrict it

Class II:
Present extracellular Ag
Only on professional APC
Presents 13-25 AA peptides, ends of groove open

Question 2

Properties of MHC?

Answer 2

Ag lies in groove

Can bind range of different peptides

T cell receptor (TCR) binds both MHC and peptides
So T cell can only recognise peptide and when combined with MHC

Question 3

How is diversity in MHC affinity achieved?

Answer 3

Each MHC molecule can bind range of peptides but not all

Different MHC alleles bind different range of peptide sequences
More different molecules = larger range of peptides able to be presented

Allows dealing with breadth of different pathogens types and preventing immune evasion

MHC genes codominant in expression so both parents’ alleles expressed equally

Question 4

How many genes for MHC class I?

Answer 4

3
HLA-A
HLA-B
HLA-C
Individuals have 6 class I genes, 3 from each parent

Question 5

How many genes for MHC class II

Answer 5

3
HLA-DP
HLA-DQ
HLA-DR
There can be 2 copies of HLA-DR
Each individual has 6-8 class II genes, 3-4 from each parent

Question 6

What is an MHC Haplotype?

Answer 6

The set of MHC alleles present on each chromosome

Foreign MHC molecules on a graft activate recipient T cells and cause rejection

Need to match haplotypes between recipients and donors as much as possible

Question 7

Properties of MHC polymorphism?

Answer 7

Highly polymorphic
5000 alleles in population
Most polymorphic genes in mammals
V unlikely that 2 individuals will have the exact same haplotypes
There will always be at least one person in the population that can present any particular antigen

Remember the weird smelly t shirt guy 🐮 (? - 🦑)

Question 8

What does MHC class I present to?

Answer 8

Intercellular Ag presented to Cytotoxic T cells, which can only see Class I presented antigens and express CD8 on their surface - which stabilises class I interactions
Kill cells with infected by intracellular pathogens

Question 9

What does MHC class II present to?

Answer 9

Extracellular Ag presented to Th and Treg cells
Th and Treg only see Ag presented by MHC class II, express CD4 on the surface - which stabilises class II interactions
Coordinate immune responses

Question 10

How are extracellular Ag presented?

Answer 10

Professional APC phagocytose proteins from the extracellular environment
Then attach them to MHC class II molecules and present them on their surface

MHC class II acts to display the extracellular environment to Th and Treg cells

Question 11

What is important about DC and T cell interaction?

Answer 11

DC tell naïve T cells whether to activate or not

DCs are immune sentinels present in barrier tissues and express PRRs (like all innate cells) and do not kill (unlike macrophages)

They scan for infection via PRRs and sample for antigens
Then take Ag to lymph nodes to talk to T cells (macrophages stay at infection site)

Question 12

What are the life phases of a DC?

Answer 12

Sampler:
In tissues before attack
-take up and spit out extracellular fluid and molecules
-express PRRs for detection of (P/D)AMPs
-not good at presenting Ag (good as mostly presenting self antigens)

Traveller with cargo:
After detection of danger signals via PRRs, or cytokines (eg TNF-alpha)
-takes in more environmental molecules/Ag
-stops sampling environment
-carries antigen to Lymph node to present them to T cells

Mature presenter of antigens in LN
-naïve T cells circulate LNs and interrogate DC to see if presenting an Ag they recognise
-Good at presenting Ag
-upregulates MHC class II
-upregulates molecules required for signal 2 to T cells (B7 or CD80/CD86)

Macrophages activate their stages in parallel

Question 13

What signals are needed for T cell to activate?

Answer 13

Signal 1- communicated Ag specificity
MHC-Ag comes interacts with TCR
Tells T cell that it recognises Ag presented by DC

Signal 2- costimulation/danger signal
Danger signals (PAMPs l) upregulates B7 (CD80/86) on APC
B7 signals to T cell via CD28

Presence of B7 tells T cell that it is recognising an Ag from a microbe and it should respond

Question 14

What is caused by no signal 2/lack of B7

Answer 14

No danger signal
Tells T cell that it is recognising a non dangerous Ag, and that it shouldn’t respond - T cell deactivated or dies

Question 15

Why one cell one receptor?

Answer 15

If T and B cells have more than one receptor:
Pathogen specific receptor created (good, cell kept alive)

And if then the same cell were to create a self specific receptor it would then be destroyed/deactivated - causing the loss of that pathogen specificity

Question 16

CTL MHC interaction properties?

Answer 16

CTL only recognise Ag presented by MHC class I (present on all nucleated cells, displays intracellular antigens)

The MHC class I/Ag complex identifies infected cells and allows for precise killing by CTL

Question 17

DC APC properties?

Answer 17

Good at activating Naïve T cells by travelling to Lymph nodes

Question 18

Macrophage APC properties?

Answer 18

Activated Th cell goes to infection site
Macrophage asks for help by presenting Ag (tells Th cell that infection is still present)
Th cell responds by producing IFN-gamma

Question 19

What does IFN-gamma do?

Answer 19

Produced by Th cells (might be more cell types too) after MHC class I/Ag signal from APC macrophage at infection site

IFN-gamma causes increased macrophage activation (see earlier cards)
Activated macrophages produce cytokines (eg TNF-alpha) which signals to NK cells and neutrophils (NK cells in turn produce more IFN-gamma causing a feedback loop)

Question 20

B cells APC properties?

Answer 20

MHC-Ag interaction important for T cell activation, but B cells are allowed to recognise unaltered Ag

This is because B cells require permission from activated Th cells to gain full effector function
Activated Th cells have passed the DC test and are assumes to be pathogen specific and so can decide if B cells are Ag specific

Question 21

Differences in T-dependent and T-independent B cell Ab response?

Answer 21

T-dependent:
Full effector functions
Can switch isotype (Fc region of Ab that defines function)
Affinity maturation- can increase its affinity for Ag

T-independent:
Limited effector function
No isotype switching
No affinity maturation
Stimulated by repeating epitopes
Usually raised against carbohydrates or non-proteins

Question 22

How do Th cells test B cells?

Answer 22

B cell presents Ag to activated Th cell
If T cell recognises then that means Ag comes from pathogen
Th cell then gives permission to respond

Question 23

How do B cells take up extracellular Ag in order to act as APC?

Answer 23

Receptor mediated endocytosis

Question 24

Difference in T and B cell activation in first and later Ag encounters?

Answer 24

First Ag encounter is the crucial one in control and so naïve T cells are difficult to activate

Activated T cells are assumed to be pathogen specific so not dangerous

Experienced T and B cells easier to activate - requirements less stringent

Question 25

Immune memory properties?

Answer 25

More pathogen specific T and B cells

Memory T and B cells easier to activate

Memory T cells can be activated by more APC types (naïve only activated by DC)

Memory T cells patrol tissues focusing on location of last infection- don’t need to be activated in LN

Memory T and B cells have established effector functions

Question 26

How are immune responses resolved?

Answer 26

As infection clears:
Danger signals reduce - innate cells lose activation signals
Antigen reduces - innate cells can no longer activate T and B cells as they can no longer see Ag
Immune regulatory networks develop- Treg cells and inhibitory cytokines (eg IL-10)

Resulting in:
Innate cells die or return to rest state
Majority of T and B cells die with no Ag
Some T and B cells survive and become memory cells