Immune activation, helper cells and regulation

Question 1

Class I,II and III antigens

Answer 1

Class I = HLA-B,C,A
Class II
Class III = HLA-DP, DQ, DR

ClassI and II code for peptides that are transmembrane molecules that appear on the surface of our cells

Question 2

Where are class II HLA molecules found?

Answer 2

On B cells and specialised antigen presenting cells
Co-dominant
polymorphic
Present peptides to CD4 T cells

Question 3

Where are class I HLA molecules found?

Answer 3

On virtually all nucleated cells
Co-dominant
Polymorphic
Present peptides to CD8 T cells

Question 4

Why don’t we all respond in the same way to infectious agents

Answer 4

we all don’t have the same HLA surface antigens

Question 5

T cell antigen recognition process

Answer 5

Very similar for CD4 and CD8 T cells but

• With class I MHC the peptide is presented to the TCR which recognises the peptide, the the CD8 molecule which recognises a conserved non-polymorphic region of HLA ABC, so in order for recognition to take need both the T cell receptor and the CD8 molecule
• Pretty much the same thing happens with class II MHC’s but CD4 instead of CD8

CD3 which is associated with both the receptor complexes signals to the insides of the cells to tell them something has happened

Question 6

Patient with defect in TAP (transmembrane antigen presenting) genes

Answer 6

Poor endogenous antigen presenting (can’t get proteins out of the endoplasmic reticulum?)
Low HLA-A, B and C
Few CD8 T cells and normal CD4 T cells
Recurrent respiratory viral infections

Question 7

What do the symptoms of patients with TAP deficiency tell us?

Answer 7

HLA classI is required for CD8 T cell development

CD8 T cells are important in viral infections

Question 8

How does my immune system know to respond to viral peptides and not to self peptides? when presented to CD8 cells

Answer 8

When we are making our immune system we can generate our receptors in both B and T cells against a very wide range of different antigen shapes including our won self antigens
Use of accessory molecules: Adhesion, co-stimulateors, cytokines

Question 9

Adhesion molecules

Answer 9

Selectins 
- Weak interactions 
- Direct cell traffic around body 
- like velcro 
Intergrins 
- Strong cell-cell adhesion 
- Holds cells in tissue together (tissue integrity) 
- Hold lymphocytes together for activation 
- Site specific addressins

Question 10

Weak adhesion

Answer 10

Low affinity, rapid association and disassociation

L-selectin 
- Circulating non-memory lymphocytes (high endothelial venues) 
P-selectin 
- Platelets 
- Endothelial cells - neutrophils 
E-selectin 
- Vascular endothelium 
- Induced by pro inflammatory cytokines (IL-1, TNFalpha) 
- leukocytes

Question 11

What are immunoglobulin superfamily (IgSF) molecules?

Answer 11

Ligans for intergrins

Contain Ig like domains

Question 12

Cadherins

Answer 12

Embryogenesis
Tissue development
Homophilic interactions (like to like)

Question 13

Lymphocyte activation 1st step

Answer 13

In order for T cells to respond they need totes their T cells against this shape to see whether they have sufficiently high affinity
Initial contact by selecting and inter grins to hold the cell together enough to make the test
= initial non-antigen specific way the cells are held together to test their receptors

Question 14

Lymphocyte activation: 2nd step

Answer 14

co-stimulators / checkpoint regulators 
Pairs of surface molecules expressed in cell- cell interactions 
B7 on APC with CD28 on T cells 
CD40 on B cells with CD40L on T cells 
Expressed transiently 
Modulate immune activation process

Question 15

How do Co-stimulators / checkpoint regulators help in the antigen recognition process?

Answer 15

APC takes up antigen at infectious site, theyre processed, broken down and some of the peptide antigens are presented on the MHC II? molecules on the surface
Bacterial metabolism is also releasing some PAMP’s which our immune and inflammatory system recognise as signatures of danger
These danger signals / PAMP’s up regulate the expression of B7 costimulator
When we get a T cell coming into contact with this, we have the TCR and CD4 as the antigen recognition complex, tells the T cell its recognised something, should you respond?? (signal 1, antigen specific) but the cell doesn’t respond unless it gets additional help signals which come in terms of the CD28 interacting with B7 (signal 2) T cell now realises it should produce response

Question 16

Co-stimulatirs/ checkpoint regulators in the presence of self antigens

Answer 16

Say APC ingests some non-bacterial protein, and breaks it down and presents it on the surface. Buts the PAMP’s / danger signals aren’t there to up regulate B7, so immune response won’t be initiated in t cell
The presence of signal 1 without signal 2 leads to the T cell becoming paralysed or anergic
= peripheral tolerance, when antigens become presented not in the danger context

Question 17

How are B cells surface receptor system different from T cells

Answer 17

B cell have antibodies anchored into the membranes as receptors, which can recognise a whole range of things and it doesn’t have to be presented to

Question 18

What else is needed to activate B cells?

Answer 18

Helper T cells

Question 19

How does B cell antigen presentation work?

Answer 19

Antigen has to bind with antibody on surface of B cell with enough specificity, this is not enough to activates the B cell, but in the process this leads to the B cell ingesting the material by pinocytosis antigen broken down internally, some fragments that are taken up get associated with MHC class II molecules and get expressed on the surface of the B cell
T cell then comes along with its TCR, CD4 complex and if its recognises the antigen 
B cell has expressed CD40 having taken up the antigen and is looking for the presence of CD40 ligand on the T cell if the T cell does express CD 40 ligand then that induce the T cell to up regulate the expression of B7 which interacts in turn with its complementary pair CD28 on the T cell, this effectively switches on the T cell to release a number of cytokine hormones that will influence the B cells activation. If we just got antigen recognition we wouldn't get activation of the B cell

Question 20

So b cell activation also requires two things?

Answer 20

B cell recognition and costimulator interactions in order to decide whether or not to become activated

Question 21

CD4 T cell colonel activation

Answer 21

antigen presentation in class II MHC
Need co-stimulation and cytokine hormones
proliferation and differentiation

Question 22

Cytokines

Answer 22

Small glycoprotein messenger molecules
Usually synthesised de novo
affect target cells via specific membrane receptors
paracrine (act locally) or autocrine (act on cell secreting them) and sometimes endocrine (distant action)

Question 23

Cytokine properties

Answer 23

Pleiotropic IL-4 = B cell proliferation, Th proliferation, Mast cell activation

Redundant IL-2, IL-4, IL-5 = B cell proliferation

Synergistic, IL4 +IL5 = Ab class switch to IgE

Antagonistic IFN-gamma = block IL-4 induced IgE class switch