ADAPTIVE IMMUNITY Flashcards
What is the key cell that bridges the innate and adaptive immune responses?
- Dendritic Cell
What do APCs stand for?
- (Professional) Antigen Presenting cells (Dendritic cell most important)
What are dendritic cells found in the epidermis called? -
- Langerhans cells
After antigen capture, where does the dendritic cell go?
- To draining lymph node where it processes and presents antigen
Which chemokine receptor to dendritic cells express once they are activated?
- CCR7 chemokine receptor
Which two chemokine ligands does CCR7 on dendritic cells bind to?
- CCL19 and CCL20
What are CL19 and CCL20 expressed by and which region of the lymph node?
- Expressed by lymphatic vessels in T cell region
Are naive T cells in blood also attracted to same region in lymph node?
- YES!
- Because T cells in blood also express CCR7
Do T cells need 2 signals to activate?
YES
What is the first signal that happens with the dendritic cell and TCR to partially activate it?
- TCR binding to MHC + Peptide ()processed antigen)
What is the second signal needed to activate T cells?
- Costimulation
- Receptor-ligand binding
- Capture and processing of antigen drives the second signal
What does the second costimulation signal prevent?
- Co-stimulation prevents overactivation of T cells
What is the key cell that bridges the innate and adaptive immune response?
- D.C
Does a virally infected cell have MHC-I expressed?
- It still has SOME but MHC expression is down regulated (by pathogens)
How do B cells recognise antigens?
- Through a BCR(can recognise the whole antigen and phagocytose)
How do T cells recognise antigens?
- Presentation by MHC complex molecules
How many signals do T cells need to be activated? -
2 signals
Is the TCR membrane bound?
- YES!
- Formation occurs in thymus
Are T cells tested when made?
- YES!
- To make sure they are functional (to pass positive selection)
- Negative selection- T cell actively killed
What is a good TCR?
- One that can recognise our own molecules
What are MHC molecules?
- Membrane bound proteins that display peptide antigens to T cells so that T cell can recognise and repsond to that antigen
How do class I and II MHC molecules differ?
- In the type of cells they INTERACT WITH
- The types of cells they’re FOUND ON
- Method that the peptide is loaded into peptide binding cleft (MHC processing pathway)
What are the two types of chains that MHC class I has?
- alpha chain (3)
- Non-MHC Beta-2 microglobulin (beta M) chain
What forms the peptide binding cleft (groove) of MHC class I ?
- Alhpa 1 domain
- Alpha 2 domain
What is the general binding arrangement of the peptide binding in MHC?
- floor of cleft binds peptides and walls make contact with TCR
What does the alpha 3 domain do on MHC class I?
- Binds CD8 T cell coreceptor
How many transmembrane chains does MHC class I have?
-1 transmembrane chain
How many chains does MHC class II have?-
- Polymorphic alpha chain
- Polymorphic Beta chain
What forms the binding cleft for MHC class II?
- Alpha 1 and Beta 1 domains
Which domain of MHC class II binds the CD4 T cell coreceptor?
- The non polymorphic Beta 2 domain
Can each molecule of MHC bind different peptides?
- YES!
- But only one peptide can bind at a time
When are MHC molecules stable?
-Only when peptides are bound (also need stability because T cells need time to interact with peptide)
Why must cells present MHC class I on the surface as a self peptide if not infected?
- Otherwise MHC not stable or NK cell will come and kill it
What type of T cells is the MHC class I pathway for?
- For antigens tin cytosol e.g viruses
- When IFN-gamma (pro-inflammation) present
Which cell does MHC class I act on and what is the length of peptide binding?
- Acts on CD8 T cells
- Length of peptide binding is short (8-11aa) - more closed in cleft
Which cell odes MHC class II act on and what is the length of peptide binding?
- Acts on CD4 Helper T cells
- Length of peptide binding is long (large) -10-30 aa in length (more open binding cleft)
What is the site of peptide binding in class I MHC?
- ER
What is the site of binding of peptide in class II MHC?
- Late endosome/lysosomes
Which cells are MHC class I found on?
- ALL nucleated cells
Which cells are MHC class II found on ?
- Professional antigen presenting cells (APCs) like DCs Macrophages and B cells
What is the purpose of cross presentation?
- To activate naive T cells so it can perform effector functions
What is the process of cross presentation?
- Cell is infected, DC phagocytoses it, antigens mpve from phagolysosome–> cytosol–> go through same MHC class I process
- CD8 T cell is ‘seeing’ the antigen to be activated and gets signal 2 (costimulator)
- CD8 T cells can then kill infected cells WITHOUT signal 2 from DCs
Can only DCs provide this signal 2?
- YES!
What is Wherer are peptides found for the mHC clas I I processing pathway?
- OUTSIDE of cell
What is the function of Ii in MHC class II processing pathway ?
Invariant chain that binds in MHC II peptide groove (chain and CLIP)
What is the function of HLADM in the MHC processing pathway?
- Removes CLIP and allows other peptides to bind
What are the steps in DC capture (cross presentation process)?
- Whole virally infected cell or phagocytosed parts of virus present in body–> phagocytosed pathogen–> moves antigens into cytosol–> goes through MHC class I presenting process–> Presents MHC I + viral antigen on surface + COSTIMULATORY MOLECULE
- NAIVE T CELL (CD8) ACTIVATED
- Casn go and kill any cell expressing same MHC peptide complex–> can then kill ANY abnormal body cell infected with virus
Why does cross presentation happen?
- Because naive T cells must have 2 SIGNALS to be activated and only certain DCs can provide the 2 signals
Is the MHC I binding cleft more closed or open than the mHC class II binding cleft?
- More closed–> shorter peptides
Is the MHC class II binding cleft more or less open than MHC class I?
- More open than MHC class I–> longer peptides
How many anchor points may there be in a binding groove that can bind the peptide?
- 1 or 2
What is meant by MHC is polymorphic?
- FOr each gene, there are MANY different alleles
What is meant by MHC being polygenic?
- Presence of several different related genes with similar functions
What is meant when MHC is co dominantly expressed?
- Every MHC gene that you have IS EXPRESSED
Which chains does the MHC class I gene contain?
- alpha chain (1 mhc gene)
- invariant beta microglobulin chain (non MHC gene)
How many MHC class I genes does our genome have?
- 6 (3 from father, 3 from mother)
How many genes is MHC class II encoded by?
- TWO MHC genes
1. Alpha chain
2. Beta chain
How many genes does our genome have?
- 6 or more genes
What is a haplotype?
- Group of alleles on one chromosome
What is Mhc known as in humans?
- HLA (Human Leukocyte Antigen)
What is MHC known as in mice?
- H-2
In humans, what are the MHC I genes known as?
- HLAA, HLAB HLAC
- 3 different MHC class I alpha genes
What do the 3 different MHC class I alpha genes encode for?
- Three different MHC class I alpha chains
In humans, what are MHC II genes known as?
-HLA-DR
-HLA-DP
HLA-DQ
-3 different MHC II genes for alphachain
- 3 different MHC II genes for Beta chain
Where is the variation in the MHC gene?
- Peptide binding cleft (lots of variation)
How did multiple MHC genes arise?
Thought to be duplication
Are MHC polymorphisms ACTIVELY selected for (if so, what via)?
- YES!
- Via replacement–> point mutations (substitutions)
- Change in coding sequence
- These mutations will lead to MHC alleles
What are the two ways new alleles can occur?
- Point mutations
- Gene conversion
What is MHC restriction?
- T cell must recognise SELF MHC molecule (AND PEPTIDE) to be able to recognise and respond to peptide
T cells that recognise self receive…
SURVIVAL SIGNAL
When does MHC restriction occur?
- When T cells are being formed in thymus (tested)
What are subunit vaccines?
- Only use specific peptides from virus
- Can take parts of virus and make into vaccine–> so you have protection from those parts and virus
What is the benefit and disadvantage of subunit vaccines?
- benefit: Safe for young, pregnant, elderly
- disadvantage: not strong response so must get booster shots.
How are the subunit vaccines made?
- Find the peptides that will fit into MOST people in the population’s MHC molecules
- ‘Immunodominant peptide’ - the one that most people mount an immune response against
What is an example of a subunit vaccine for disease?
- Acellular pertusis (whooping cough)
- but need repeated immunisations
- Hep B
Can MHC haplotypes influence sucdeptibility to certain disease?
- YES!
- can be a protective or a risk factor
- protective risk factor–> can prevent some antigens from binding
- Risk factor–> May display certain haplotypes better
In transplantation, what does the T cell see if rejection occurs?-
- It sees donor MHC: Peptide as self
- And sees self MHC: Peptide as FOREIGN
Which proinflammatory cytokines are release upon DC interaction with microbe?
- Cytokines - TNF-alpha
- IL-1
What are 3 functions of T cells?
- Activation of phagocytes
- Killing of infected cells
- Help for B cells
Do naive T cells have effector functions?
- NO
Once a naive T cell recognises antigen in peripheri what happens to it?
- It proliferates and differentiates into effector T cells and memory cells
What are the steps for T cell activation in naive T cells?
IN LYMPHOID TISSUE:
T cells produce cytokines (IL-2) AND express the IL-2 receptor (autocrine signalling)
- IL-2 binding causes T cell proliferation
IN PERIPHERAL TISSUES:
- Differentiation into effector T cells (CD4–> activates macrophages and CD8 –> kills infected target cells)
Do all activated T cells go to effector organs/tissues?
- NO! Some effector T cells stay in the lymph nodes–> eradicate infected cells OR give signals to B cells (antibody production)
What do naive T cells do?
- Circulate through peripheral lymphoid organs to FIND ANTIGENS matching their receptor
Which receptors/coreceptors are required on T cells that recognise ligands on APCs to allow for T cell activation of responses?
- TCR (recognise MHC on peptide antigens)
- CD4/CD8 coreceptors on T cell (recognise MHC to allow TCR complex to deliver activating signals
- Adhesion molecules –> strengthens binding of T cell-Antigen Presenting Cell
- Costimulator molecule–> binding to costimulatory receptor on naive T cell
- Cytokines
What is the recognition of MHC-associated peptides by?
- TCR + CD4/Cd8 coreceptor
- Both recognise complexes of peptide antigen and MHC molecules on APCs
Do the TCR alpha and beta chain BOTH take part in antigen recognition?
- YES!
What does the TCR recognise specifically?
- Displayed peptide and residues of MHC around peptide binding cleft `
Do the CD4/CD8 coreceptor recognise MHC at the same site to the peptide binding cleft?
- NO they recognise it at a site different to the peptide biding cleft
Which surface molecule does signal transduction by the TCR complex?
- CD3 (x3) + zeta chain
- TCR alpha and beta chain can recognise antigens but NOT TRANSDUCE BIOCHEMICAL SIGNALS
Can TCR alhpa and beta chain transmit biochem signals?
- NO! Only CD3 + zeta chain can do that
