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What does intracellular infection always result in?
cell mediated immunity (CMI) and cytotoxic T lymphocyte (CTL) and endogenous processing
What are the most effect APCs?
dendritic cells and macrophages
What is the definition of an intracellular infection?
a pathogen that lives w/in a host cell's cytoplasm and depends on host cell machinery (per esempio viruses)
What is assoc w/ endogenous processing?
degradation by proteosome, MHC-1, tapisin, TAP, ubiquitin, IFN-gamma
cytokine assoc w/ inflammation; up-regulates activities of proteosomes in endogenous processing
How are prot tagged to go to the proteosome in endogenous processing?
Transporters Associated w/ antigen Processing; recognizes digested antigen from proteosome and acts as doorway into ER lumen for digested antigen
assoc temporarily with MHC-1 via tapisin
molecular "glue" for MHC-1 prot to attach to TAP prot in ER lumen
expressed on all nuc cells (i.e. NOT RBCs)
3 isoforms of MHC-1
HLA-A, HLA-B, HLA-C
Structure of MHC-1
- alpha heavy chain w/ 3 domains
- B2 microglobulin
- TM tail on alpha-3 only
MHC-1 heavy chain structure
- alpha-1 and alpha-2: form antigen binding pocket, no TM region; stabilized by B2 microglobulin
- alpha-3: does not participate in antigen binding pocket, has TM tail to anchor to mem
B2 microglobulin of MHC-1
non-cov assoc w/ heavy chain; not genetically in MHC complex; absolutely necessary for MHC-1 to be expressed on surface
Is there recombination in HLA and B2 genes?
What characteristics of MHC-1 provide diversity?
- Polygenic: 3 isoforms for HLA
- Polymorphic: hundreds of alleles for each isoform
- Codominant expression: all products of alleles being expressed on cell surface
- Low freq of XO (reduces diversity)
Describe the peptide binding site of MHC-1
alpha-1 and alpha-2 domains fold to create a groove in which 2 alpha helical walls are surrounded by a beta floor---hot dog bun analogy
certain specifically placed amino acids in antigen peptide that bind to alpha helical groove of MHC-1 binding pocket
Peptide binding motif
allows many peptides w/ same anchor residues (does not need to be all of the AAs) to bind to the same MHC binding site
TCR must simultaneously bind to exposed AA in peptide and to polymorphic AA in MHC-1 (primarily in alpha helical walls)
MHC restricted T cell recognition
T cell recog of peptides is restricted to the certain MHC in the ind (i.e. isoforms and alleles expressed)
- determined by:
- 1. antigen peptide created w/ high freq during processing by proteosome
- 2. antigen peptide has correct anchor residues for MHC-1 present in ind
- 3. antigen peptide was chopped up into the right length (8-10AA)
- 4. specific TCRs are available in the ind
Why can't every ind have same response to an antigen? Why is this an adv?
each ind has diff alleles present for MHC-1 domains which gives a diff specificity in the binding pocket of alpha-1 and alpha-2 along with diff TCR repetoirs (VDJ rearrangment and N P disjunction)
allows evolutionary adv in species...not everyone can be killed by same pathogen!
What is the first signal for T cell activation?
binding of peptide/MHC-1 complex by TCR..results in passing of signals to CD3 complex
Why does the TCR need a co-receptor? What is it?
peptide/MHC-1 complex is not stable enough
"glue" for MHC-1/antigen/TCR complex
binds to non-polymorphic region of alpha-3 in MHC-1...aka CD8 is highly conserved; has TM tails in T cell
What is the second signal for MHC-1?
needed as second signal for CD8+T cells to become fully activated
- CD28 (on T cell); has TM tails into mem
- CD80/CD86 (on APC)
When is signal 2 needed?
only needed in T cell ACTIVATION..once T cell has been activated once, co-stimulation is not necessary
cytokine that is necessary to maintain growth and activation of T cells
Cytotoxic T lymphocytes
- effector cell of CD8+ T cells; acts as a serial killer; results in apoptosis of cell which can then trigger a cascade of other enzymatic activities:
- 1. cyt C of mit
- 2. caspases
- 3. caspase-activated DNase (CAD): causes DNA fragmentation
Who are the inducers of apoptosis produced by CTLs?
granzymes and FAS ligand
What is the role of granzymes?
proteolytic enz in cytoplasmic granules; randomly distributed until CTL bound to target cell; granules become polarized next to target cell
move into target cell and trigger apoptosis after perforins act
prot stored in granules; released from CTL and forms pores in target cell lipid bilayer mem
on surface of CTL; when brought close to target cell, Fas ligand engages Fas on surface of target cell which triggers caspase cascade leading to apoptosis
Tumor Necrosis Factor; directly kills some target cells
Natural killer cells
technically lymphocytes but does not resemble B or T cells; aka lg granular lymphocytes
part of innate system of host defenses bc considered partially active; able to perform effector functions w/o conventional activation against antigen
one of first line of defenses, hard to charac rec
How do NKs recog antigen?
NOT by MHC molecules; preferentially attach host cells w/ decreased MHC-1 expression
- activating: can recog ALL cells
- inhibiting: turns NK off when finds MHC-1 non-polymorphic regions
Why are NKs sometimes beneficial against viruses?
some viruses try to beat the host defenses by killing host MHC-1 molecules; w/o MHC-1 molecules present, NK are left on (inhib recep cannot bind to anything!), NK attack viruses
What are the functions of NK?
- 1. cytolysis
- 2. cytokine prod (IFN-gamma) to activate macrophages
- 3. not MHC-1 restricted