Antigen presentation Flashcards
What is the Take home message for MHC Class I expression?
What’s going on INSIDE the cell; displays endogenous peptides to killer T cells; expressed on all nucleated cells
What is the take home message for MHC Class II?
what’s going on OUTSIDE the cell; displays exogenous peptides to helper T cells; expressed only on antigen presenting cells
Professional APC
- Activated dendritic cells
- Activated macrophages
- Activated B cells
Two-signal activation model:
What are the two signals?
Do all T cells need co-stimulation (second signal)?
- Signal 1: Defines specificity
APC is carrying a particular antigen and MHC on its surface
T cell has a T cell receptor which recognises all the amino acids on that peptide and is specific to that paticular peptide
Prologned interation between APC and T cell by cell-cell contact or mediators
- Signal 2: Mediates proliferation
B7.1/B7.2 ON APC (CD80/CD86) and CD28 on the T cell
Allows T cell to go through proliferation and migration to the site of infection
This CD28-mediated co-stimulatory signals extends to virtually all T-cell subsets
From the diagram:
MHC class II is carying carrying peptide from an extracellular pathogen, it migrates to the lymph node and interacts with T cells. The T cell receptor specifically recognises the peptide. The second signal is costmulation which is usually between B7 and CD28
Activated dendritic cells (DC)
- Most important APC – activate naïve T cells
- DC found all over the body, especially at the interface between the body and the outside world (skin, respiratory tract, genitouninary tract, gut ect)
- Function as spies – the collect information about the enemy and take it back to base
- In normal tissue, DC are heavy drinkers – take up four times their volume per hour, process the antigens then spit it out
- Resting DC: express low levels of MHC II and B7 – no good at activating naïve T cells
What do dendritic cells do during an infection?
During an infection, DC recognise invading pathogens e.g. LPS on a gram negative bacterium or cytokines and become activated
DC now STOP drinking, leave the tissue through lymph vessels and head to the lymph nodes
What are is the function of resting dendritic cells?
Resting DC keep stores of MHC II in their cytoplasm
During the journey to the activated DC:
- loads these MHC II with antigens from the site of infection
- upregulates MHC I expression and loading
- displays exogenous (bacterial) and endogenous (viral) antigens
- increases production of B7 (signal 2)
What do dendritic cells do at their destination (when they get to the lymph node)?
- MHC II are fully loaded; exogenous peptides on display at the cell surface
- MHC I are fully loaded; endogenous peptides on display at the cell surface
- B7 expressed at cell surface
- Activated DC in the lymph node are equipped and ready to activate naïve T cells
Dendritic cells retain a snapshot of the infection site:
Which T cells will be activated?
- Activated DC stop drinking before they set out on the journey to the lymph node
- They want to make sure that they activate the appropriate T cells – T cells that we need to help fight the infection
- DC take these antigens from the site of infection to the lymph nodes (like military bases) where the naïve T cells (the generals) are hanging out
- Only the T cells that recognise the invader will be activated, proliferate and migrate to the site of infection
What triggers DC migration?
Cytokines (TNF) trigger DC migration, so DC will only travel to the lymph node to present antigen to T cells when there is a battle on
DC respond in appropriate numbers:
How do Dendritic cells attract progenitor cells?
What does the number of T cells activated in the lymph node depend on?
- DC will only set off for the lymph nodes if they have detected battle cytokines
- Before the DC leave, they recruit replacements
- Activated DC make chemokines that attract progenitor cells to the site of infection
- These cells will become DC and can be activated and travel to lymph nodes to amplify the response
more infection = more cytokines produced by DC = more DC set off
mild infection = few cytokines produced by DC = few DC set off
- The number of T cells activated in the lymph node depends on how many DC travelled to the lymph node
The magnitude of the immune response is tailored to fit the severity of the infection
Activated macrophages: How do they function as sentries in tissues?
- Rubbish collectors
- Antigen presenting cells
- Efficient killers
They stay at the site of infection, they repeatedly stimulate specific T cells
What do macrophages need before they can present antigens?
Macrophages also need battle signals (IFNγ) before they are any good at presenting antigens
Give an anology that compares Dendritic cells to Macrophages
- DC are spies: collect information and leave
- Macs are soldiers: stand and fight
What hapens at an Immunological synapse?
- This is where a biochemical signal is transduced from the APC to the T cell via the T cell receptor
- A very tight connection is formed between the APC and the T cell, involving cytoskeletal rearrangements
- There is a ring of adhesion molecules and the signalling happens in the middle
If it is a CD4+ T cell its going to get information from the dendritic cell regarding type of infection and the CD4+ T cell can change its genetic program using different transcription factors to tailor the immune response to where that pathogen is
Explain T cell receptor signalling cascade:
What is Zeta-chain associated protein kinase 70?
What is the enzyme responsible for?
- A cytoplasmic protein of 70 kDa. It is part of the T-cell receptor (TCR)/CD3 complex situated on the plasma membrane of T cells that recognises the antigen
- ZAP-70 (on intracellular side of TCR) is responsible for the initiation of all the different pathways in the T-cell signalling cascade, and plays a critical role in the development of cell-mediated immune response (signal transduction)
- Leads to transcription factors (e.g. NF-κB )binding to DNA and activating the expression of certain genes
How do CD8+ T cells function?
- Cytotoxic CD8+ T (need to be activated by an APC and by helper T cells*) cells function by recognizing peptide bound to MHC Class I on APC, i.e. dendritic cells (DC), macrophages, and B cells
- The peptide has been endogenously processed either directly (derived from viral genes, such as HIV) or indirectly through cross-presentation (derived from dead bacterially infected cells, i.e. MTb).
- This causes the release of cytotoxic granules (perforin and granzymes) from the CD8+ T cell which then cause lysis and apoptosis of infected target cells.
How does CD4+ T cells function?
- T cells recognize peptide fragments that have been processed and presented on MHC Class II by APC
- CD4+ T cell activation results in the secretion of cytokines that help and regulate other cells
- The pattern of cytokine expression defines the subsets of CD4+ T cells: Th1, Th2, Treg, and Th17 cells:
- Th1 cells secrete interferon gamma (IFN-y) and create a milieu in which key cytotoxic effectors—macrophages, natural killer cells, and cytotoxic CD8+ T lymphocytes—are activated, generating cell-mediated immunity.
- Th2 cells secrete IL-4 and IL-10 (and other cytokines) and help antigen-primed B lymphocytes differentiate into plasma cells and secrete antibodies, the effector molecules of humoral responses. Associated with allergy
- Treg cells secrete IL-10 (Interleukin 10) and transforming growth factor beta (TGF-β) to calm down immune responses.
- Th17 cells represent a wide variety of recently described cells involved in inflammation, fungal and autoimmune disease
