Chapter 13 - I Flashcards
Immune response to viral Infection
the adaptive immune response to viruses involve both antibody the CTL responses
The goal is to prevent infection of more cells by virus
Viruses: extracellular state
- its an inert particle –> Ab response is appropriate
: to neutralize virus before it binds and infects cells
If intracellular state - replication nucleic acids
–> CTL response is appropriate to kill cell to disrupt virus replication before it is complete
Immune response to viral Infection
Intracellular viruses (replicating form) - appropriate response is CTL response
Goal : sacrifice the infected cell so that the virus replication cycle can be halter and prevent spread
Main types of cells involved:
- CTL-P which are activated to CTL
- TH cells to providing IL-2 needed for CTL proliferation
- Dendritic cells to activate TH cells and CTL-P
CTL- P - Cytotoxic T lymphocyte = precursor - a naive T cell that needs to change gene expression in order to gain its effector function
Innate Responses to viral infections -I
Internal TLRs recognize structures like uncapped RNA and double-stranded RNA which are typical in virus infections and not typically found in uninfected cells
Cellular location of PRR:
- extracellular
- cytosolic
- endosomal
Innate Responses to viral infections - II
Activated TLRs induces the expression of type I interferon genes (IFN a/b)
- IFN a/b bind to a common receptor found on neighboring uninfected cells and triggers signaling response
- this results in neighboring cells shutting down protein synthesis so that if they get infected the virus can’t replicate
cells also dies because protein synthesis is essential for life but better then getting infected
Innate response to viral Infections
- virus in tissue
- engulfed by dendritic cells near infection site
- initiates exogenous peptide presentation pathway or cress presentation
- can present on both MHC class 1 and 2 and activate both CTL-P and naive TH cells
or
- infect non-dendritic cells of body
- virus replication begins
- Viral genome replication begins
- some kVirus proteins digested by protostome (endogenous)
- Peptides displayed on MHC I
- activated CTLs find and kill cell
Innate response to viral Infections
CTL responses
- cells infected with virus will display a peptide from the virus on MHC class 1
- this identifies the infected to the CTL for cell-mediated killing
The problem
- cell that is not professional APCs (eg dendritic cells) will not activate CTL-P
- the infected cells may not be in a lymph node or spleen
- CTL-Ps hand out in lymph node and spleen waiting for dendritic cells to activate then
- these infected cells do not have co-stimulatory molecule B7 that is required to provide signal 2 to T cells
- if CTL-P receives signal 1 from these infected cells it will become anergic
Viral Peptides and endogenous pathway
MHC class 1 endogenous pathway - nucleated cells
eg if a muscle cell is infected with a virus, as the virus replicates and expresses its genome, the virus protein may be degraded by the proteasome
Peptides are presented onto MHC class 1 through the endogenous pathway
MHC class 1 -viral peptide display on the cell surface
MHC class 1 can’t tell the difference between self-peptide and pathogen peptide
Innate immune response to viral infections
- Muscle cell is infected and presents viral peptide on MHC class 1 but it does not express B7- costimulatory molecules
Naive CTL-P that interacts with it will become anergic
- need mature CTL to do this
would be bad - the virus continues to replicate and infect other cells
But CTL-Ps are not in tissues - they are in lymph node
Dendritic Cells and viral Infection
In the body the most important APC of naive T cell is dendritic cell
there are many different subset of dendritic cells and some derived from common myeloid precursors and some are derived from common lymph precursors
Dendritic cells express both MHC class 1 , 2 and co-stimulatory molecule B7
Immature dendritic cells are very phagocytic but once they have started, they matures quickly and migrate to lymph node to activate naive T cells
They migrate to where the CTL-Ps are hanging out to activate them
Dendritic Cells and viral Infection
When necessary (initiating CTL response) dendritic cells can display extracellular proteins on MHC class 1 - corss presentation
dendritic cells have lagre SA to activate many naive T cells
Cross presentation is needed because very few viruses can infect dendritic cells, so no cytoplasmic viral peptides will be inside the dendritic cell for the endogenous pathways. Even if they can invade, they are degraded in phagosome - need protease to get peptide?
Dendritic Cells and viral Infection
Exogenous pathway: virus particle is digested by protease
The dendritic cell receives some signal that tells that it needs to do x presentation
the signal is cytokines from infected cells
Change-over event: some fragments are diverted to the proteasome in cytoplasm to be presented on MHC class 1
endogenous uses proteosome
Dendritic Cells and viral Infection
Endogenous pathway: peptides processed by proteasome are ultimately loaded onto MHC class 1
Peptides that are further processed in phagolysosome continue to be loaded onto MHC class 2
key outcome: dendritic cells display the viral peptide on both MHC class I and II and can simultaneously activate both CTLs and TH cells respectively
CTL activation
Dendritic ability to display both MHC class I and Ii proteins, the same dendritic ell could be activating both TH cell and CTL
CTL activation
Since CTLs kill self cells it is important that these are activated only when needed
CTL-P requires 2 signals for activation and a lot of IL-2 for differentiation into functional CTL
It can make IL-2 but needed extra from TH cells
the dendritic cell does its part by providing cytokines as well
CTL activation
CTLs are activated in lymph node or spleen then leave to patrol the body looking for infected cells with virus
at site of infection there is inflammation - CTL leaves blood vessel and enter into tissue - like neutrophils
The TCRs of CTLs scan the surface of each cell looking for the same MHC class I peptide complex
when it finds the atger cell, it releases perforin to punch holes in membrane, and granzyme (proteases) - these trigger the infected cell to undergo apoptosis
Takes ~ 45-60 mins for infected cell to be killed
after killing the infected cel, the CTL disengage from dead cell and start to look for another target
