Immune activation, helper cells and regulation Flashcards
Class I,II and III antigens
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
Where are class II HLA molecules found?
On B cells and specialised antigen presenting cells
Co-dominant
polymorphic
Present peptides to CD4 T cells
Where are class I HLA molecules found?
On virtually all nucleated cells
Co-dominant
Polymorphic
Present peptides to CD8 T cells
Why don’t we all respond in the same way to infectious agents
we all don’t have the same HLA surface antigens
T cell antigen recognition process
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
Patient with defect in TAP (transmembrane antigen presenting) genes
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
What do the symptoms of patients with TAP deficiency tell us?
HLA classI is required for CD8 T cell development
CD8 T cells are important in viral infections
How does my immune system know to respond to viral peptides and not to self peptides? when presented to CD8 cells
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
Adhesion molecules
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
Weak adhesion
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
What are immunoglobulin superfamily (IgSF) molecules?
Ligans for intergrins
Contain Ig like domains
Cadherins
Embryogenesis
Tissue development
Homophilic interactions (like to like)
Lymphocyte activation 1st step
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
Lymphocyte activation: 2nd step
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
How do Co-stimulators / checkpoint regulators help in the antigen recognition process?
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
Co-stimulatirs/ checkpoint regulators in the presence of self antigens
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
How are B cells surface receptor system different from T cells
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
What else is needed to activate B cells?
Helper T cells
How does B cell antigen presentation work?
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
So b cell activation also requires two things?
B cell recognition and costimulator interactions in order to decide whether or not to become activated
CD4 T cell colonel activation
antigen presentation in class II MHC
Need co-stimulation and cytokine hormones
proliferation and differentiation
Cytokines
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)
Cytokine properties
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
