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Immunology and Infection > MHC > Flashcards

MHC Flashcards

1
Q

what does a T cell require to become activated?

A
  • need to have an antigen presented to them by an APC
  • the antigen is presented on MHC proteins
  • which is recognised by the TCR
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2
Q

what is MHC class I?

A
  • cell is infected with intracellular pathogen

- proteins broken into peptides and presented on the surface by MHC class I

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3
Q

what recognises MHC class I?

A

CD8 T cell

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4
Q

what is MHC class II?

A
  • extracellular pathogen, responds and takes it up
  • puts in an intracellular vesicle
  • digests into peptides
  • presents on MHC class II
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5
Q

what recognises MHC class II?

A

CD4 T helper cell

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6
Q

what is MHC?

A
  • a gene cluster
  • encodes MHC class I and II proteins
  • main role is to present the antigens on the cell surface
  • peptide-MHC complex is recognised by TCR
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7
Q

what is MHC class I expressed by?

A

nucleated cells

- any cell with a nucleus could be infected by a virus

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8
Q

what is MHC class II expressed by?

A

antigen presenting cells eg dendritic cells, macrophages, B cells

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9
Q

what is the structure of MHC class I?

A
  • 2 subunits
  • alpha chain with 3 domains
  • B2 microglobulin (B2M)
  • peptide binding groove is formed by alpha chain, a1 and a1 domains
  • alpha chain has extensive polymorphism
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10
Q

what is the structure of MHC class II?

A
  • has 2 subunits
  • different domain structure
  • alpha and beta chain are encoded in MHC gene cluster
  • peptide binding groove formed by a1 and B1 domains
  • extensive polymorphism shown in both a and B chains
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11
Q

how does TCR interact with MHC?

A
  • TCR interacts simultaneously with both MHC and associated peptide
  • TCR recognises peptide in the context of MHC
  • T cell only activated if peptide is presented by MHC
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12
Q

how does MHC bind to peptides?

A
  • peptide binding groove formed from 2 alpha helices, lie on top of a B sheet, forms the cleft
  • for both MHC I and II
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13
Q

how does peptide bind in MHC class I?

A
  • peptide is constrained at both ends by invariant amino acids
  • bulky chains at the N terminus stop the peptide going further
  • class I can only bind short peptides (8-10 aa)
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14
Q

how does peptide bind in MHC class II?

A
  • open peptide binding groove
  • peptide can protrude at either end
  • can be 13+aa
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15
Q

how is MHC polygenic?

A

every person expresses several different variants

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16
Q

how is MHC polymorphic?

A

human population contains many different variants (ie alleles)

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17
Q

where is the human MHC?

A

gene cluster on chromosome 6

- Human MHC genes = HLA (human leukocyte antigen) genes

18
Q

what gives MHC such great diversity?

A
  • each of express 3 different types of MHC I alpha chain from each chromosome 6
  • each person expresses 3x different MHC II a and b genes from each chromosome 6
  • MHC genes are the most polymorphic gene known
19
Q

how many MHC does a person have?

A

3x HLA per chromosome x2 chromosomes = 6 MHC per person

20
Q

where does allelic variation localise?

A

the peptide binding groove

21
Q

how do variations effect the peptide binding groove?

A
  • polymorphisms alter shape of peptide binding groove
  • altered shape means different variants bind different peptides
  • peptides bind to particular MHCs through ‘anchor residues’
22
Q

what do polymorphisms in MHC form?

A

distinct pockets that peptide anchor residue fits into

23
Q

what is at the C terminus of the peptide?

A
  • hydrophobic amino acids
  • tyrosine residues are bulky side chains
  • interact with the pockets known as anchor residues
  • stick the peptide down into the MHC
24
Q

whats difficult for pathogens as a result?

A
  • difficult for pathogens to evolve to be non-presentable

- if we all shared one MHC it would be able to evolve

25
Q

what are the 3 stages of presenting peptides from cystolic proteins on MHC class I?

A
  1. break down proteins into peptides
  2. transport of peptides into ER
  3. peptide coating onto MHC class I
26
Q

how are proteins broken down into peptides during stage 1 of presenting peptides on MHC class I?

A
  • proteins digested by proteasome
  • all cells express constitutive proteasome
  • IFNy induces immunoproteasome formation
27
Q

what is the structure of the constitutive proteasome?

A
  • 20s catalytic core = 28 subunits, protease activity

- 19s regulatory caps directs cystolic proteins to core

28
Q

what is the role of the immunoproteasome?

A
  • fires out better peptides and fires them out faster
  • new catalytic core proteins = increased cleavage after hydrophobic residues
  • new regulatory cap proteins = faster peptide release
29
Q

how are peptides transported into the ER in stage 2 of antigen presentation on MHC class I?

A
  • MHC I co-translationally translocated into the ER membrane
  • active transport of peptides by ER membrane TAP1 and TAP2 proteins
  • have a preference for peptides with hydrophobic residue at the C terminus
  • constitutively expressed is IFN inducible, can be increase during infection
30
Q

what is peptide coating onto MHC class I in stage 3?

A
  • stable peptide is essential for cell surface MHC expression
  • alpha chain folds and binds to B2M
  • some ER peptides are too long
  • form a peptide loading complex (PLC)
31
Q

why is stable peptide binding essential for cell surface MHC I epxression?

A
  • MHC proteins are unstable when not bound to peptides or weakly bound
  • dont want the peptide to dissociate
32
Q

what are long peptides trimmed by MHC I loading?

A

trimmed to 8-10 aa by ER amino peptidase

33
Q

what is the peptide loading complex (PLC)?

A
  • chaperone proteins, bind to MHC
  • Tapasin, binds to MHC and TAP, pulls MHC close
  • PLC performs peptide editing i.e remove low affinity peptides
  • PLC ensures only high affinity peptides stably bind MHC
34
Q

what are the 4 stages of MHC class I presentation?

A
  1. peptide generation in acidified endosome
  2. movement of MHC II to acidified endosomes
  3. invariant chain cleavage to CLIP
  4. HLA_DMs promotes stable peptide binding in MIIC
35
Q

how is a peptide generated in acidified endosomes in MHC class II stage 1?

A
  • convert the pathogens/proteins into peptides
  • proteasomes not present in vesicle
  • early endosome, fuse and acidify it
  • acidic pH activates acid cysteine proteases eg cathepsins
36
Q

how are MHC II moved to acidified endosomes during presentation stage 2?

A
  • MHC II co-translationally translocated into the ER membrane
  • dont want MHC II to bind peptides prematurely, prevent this with the invariant chain
37
Q

how does the invariant chain prevent MHC II and peptides binding prematurely during stage 2 of presentation?

A
  1. block MHC II peptide binding groove and stops peptide binding in the ER
  2. directs MHC II from ER to low pH endosomes towards vesicular proteins
38
Q

what is invariant chain cleavage to CLIP in stage 3 of MHC II presentation?

A
  • MHC II associated with invariant chain = vesicle acidifies
  • invariant chian degrades apart from the CLIP fragment
  • acid vesicle is called the MIIC
  • moving towards to acid endosome
39
Q

how does HLA-DMs promote stable peptide binding in MIIC in stage of MHC II presentation?

A
  • HLA_DM is a MHC II like molecule
    HLA-DM promotes:
    1. removal of CLIP fragment from MHC II binding groove
    2. peptide editing
40
Q

why do you need cross presentation?

A
  • naive CD8 T cells needs to be activated by MHC I on a dendritic cell
  • good if you have a virus that infects a DC
  • problem if the virus doesnt affect a DC, need cross presentation from the MHCII pathway to the MHC I pathway
41
Q

what cells can cross present?

A

cross presentation pathway is unique to the DC

42
Q

how do cross presentation work?

A
  • virus taken in by endocytosis into an endosome which becomes acidified and broken into peptides
  • dendritic cells express endosomal channel protein Sec61
  • shuttles peptides from the endosome into the cytosol
  • enters the class I pathway

Immunology and Infection (13 decks)

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