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Basic Immunology- Module 1 > MHC class I and antigen recognition > Flashcards

MHC class I and antigen recognition Flashcards

1
Q

Why does there have to be a rapid response to MHC class I?

A

viral infection cycles can be short-4 hours, so need to identify and kill infected cell before virus release

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2
Q

What breaks up the proteins in to peptides to go into the endoplasmic reticulum?

A

proteasome

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3
Q

What is the transporter for peptides into the endoplasmic reticulum?

A

TAP1 and TAP2

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4
Q

What cells are capable of cross presentation?

A

DCs and macrophages

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5
Q

In addition to the structural cell surface, what else does the HLA region encode?

A

peptide loading functions- TAPS and LMPs

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6
Q

What is TAP?

A

transporter associated with antigen presentation

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7
Q

How are pMHC complexes from the ER to the plasma membrane?

A

golgi apparatus

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8
Q

What has to happen to endogenous proteins before they can be fe to the proteasome?

A

ubiquitinated

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9
Q

What is a proteasome?

A

multicatalytic protease complex made up of around 28 subunuts

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10
Q

How does gamm inteferon affect the proteasome?

A

induces expression of alternative beta subunits creating an immunoproteasome

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11
Q

What alternative beta subunits does IFNy induce in the proteasome?

A

PSMB10; LMP2 and LMP7; LMP10; PA28

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12
Q

What is the function of proteasome activating molecule (PA28) iniduced by gamma interferon?

A

increased release of cleaved peptides

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13
Q

Where do immunoproteasomes preferentially cleave peptide bonds?

A

after hydrophpboic or basic residues

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14
Q

Why do immunoproteasome preferntially cleave after hydrophobic or basic residues?

A

preferred by MHC class I for binding

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15
Q

What type of transporter is TAP?

A

ATP dependent (ATP binding cassette- ABC family of transporters)

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16
Q

What are carbxoxyl terminla amino acids ?

A

hydrophobic or basic

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17
Q

What is the specificty of a given allelic MHC molecule for different peptides?

A

can bind numerous different peptides; each MHC allele binds a different set of peptides

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18
Q

What is the function of the diversity of MHC I,II within a species?

A

helps protect from new pathogens

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19
Q

Where are most polymorphic residues located in the MHC molecule?

A

in the peptide binding cleft

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20
Q

What is found within the deep pockets of the MHC molecules?

A

anchor residues

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21
Q

What is the function of the anchor residues?

A

where peptides are bound

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22
Q

What is the converved anchor residue?

A

hydrophobic (basic occasionally)

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23
Q

What amino acid sequence does the MHC-I groove correspond to?

A

contiguous amino acid sequence formed by the N-terminal region of a single subunit or heavy chain

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24
Q

What amino sequence does the MHC-II groove correspond to?

A

juxtaposition of hte N-terminal regions of 2 MHC encoded alpha and beta chains

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25
Q

What is the difference between the membrane-proximal regions of the MHC-I and MHC-II molecules?

A

although in both it is a conserved domain that are homologous to the Ig constant region, in MHC-I, one is the heavy chain and the other is beta microglobulin, whereas in MHC-II there is an alpha subunit and beta subunit

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26
Q

What mediates proteolysis in the cytosol?

A

proteasome

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27
Q

What is the function of cross-presentation?

A

allows dendritic cells to present antigen to CD8 T cells even if the virus does not directly infect dendritic cells

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28
Q

What is the activation of naive T cells through cross presentation called?

A

cross-priming

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29
Q

What is the structure of the proteasome?

A

20S catalytic core which consists of 4 multiple subunit rings with 2 19S regulatory caps on either end

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30
Q

What are the 2 outer rings of the proteasome core formed of?

A

alpha subunits

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31
Q

What are the 2 inner rings of the proteasome core formed of?

A

beta subunits

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32
Q

Which parts of the proteasome make up the active proteolytic components?

A

some of the beta subunits of hte inner rings- b1, b2 and b5

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33
Q

What can change the active beta subunits of hte proteasome?

A

IFNy

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34
Q

What are the variants of hte active beta subunits induced by IFNy?

A

LMP1; LMP2 and MECL1

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35
Q

What are proteasomes that contain LMP1; LMP2 and MECL1 called?

A

immunoproteasomes

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36
Q

What si the function of the 19S caps of the proteasome

?

A

recognises ubiquitin-conjugated proteins targeted for degradation and the other prevents proteins from exiting hte proteasome prematurely

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37
Q

What does the 19S that recognises the ubiquitin-conjugated proteins do?

A

has deubiquitinase activity and unfoldase actiivty

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38
Q

What does the unfoldase activity of hte 19S subunits require?

A

ATP

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39
Q

What type of MHC molecules is the proteasome used for?

A

MHC-I

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40
Q

What is different about the cleavage of proteins by the proteasome and immunoproteasome?

A

the immunoproteasome has altered enzymatic specificity meaning there is increased cleavage of polypeptides after hydrophobi residues and decreased after acidic residues- this gives carboxy-terminal resiudes that are preferred anchor resiudes for MHC-1 and for transport by TAP

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41
Q

Aside from changing the active constituents of the proteasome, what other effect does IFNy have on the proteasome?

A

induces expression of PA28 proteasome-activator complex

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42
Q

what is the function of PA28?

A

binds to the 20S proteasome in place of either of hte caps and increases rate at which peptides are released

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43
Q

What are the different vesicles in the process of endocytosis?

A

early endosomes; late endosomes and lysosomes

44
Q

Why do cathepsins work in lysosomes?

A

work at an optimum pH of 4-4.5

45
Q

What happens to proteins that have been degraded in macrophages?

A

highly degradative cell- cleavage results in very short peptides and free amino aicds - replenish tRNAs for protein synthesis

46
Q

What happens to proteins that have been degaded in APCs?

A

less proteolytically active- larger intermediates which form the main source of ppetides for MHCII binding

47
Q

Where does MHC-I molecules bind peptides?

A

in the ER

48
Q

What proteins are responsible for protein transport into the ER?

A

TAP1 and TAP2

49
Q

What does the protein transport by TAP require?

A

ATP

50
Q

What is the specificity of TAP1:TAP2?

A

transports peptides between 8-16 amino acids and those that have hydrophobic or basic residues at hte carboxy terminus: same features as peptides bound by MHC-I

51
Q

What happens to proteins that are too long for binding to the MHC-I molecule?

A

further trimmed by endoplasmic reticulum aminopeptidase associated iwth antigen processing (ERAAP)

52
Q

Which terminus of hte protein does ERAAP cleave?

A

amino terminus

53
Q

What prevents complete degradation of peptides produced in the cytosol?

A

cellular chaperones- TCP1 ring complex

54
Q

What does folding and assmebly of a complete MHC-I molecule require?

A

associated of the MHC Ia chain first with beta2 microglobulin and then with peptide– only after MHC I has bound peptide is it released from ER

55
Q

What binds newly synthesised MHC Ia chains when it enters the ER?

A

calnexin -retains MHCI in a partly folded state

56
Q

What does MHCI bind to after beta2 microglobulin has bound to the alpha chain?

A

peptide loading complex

57
Q

What are 2 proteins in the peptide loading complex?

A

calreticulin; tapasin; ERp57

58
Q

What is the function of calreticulin in the peptde loading compelx?

A

general chaperone function like calnexin- mediates further folding of MHC and association of MHC-1 to beta2 microglobulin

59
Q

Waht is the function of tapasin in the peptide oading copmlex?

A

forms a bridge between MHC-I and TAP allwoing the partly folded a:b2 heterodimer to wait the transport of a suitable peptide from the cytosol

60
Q

What is the function of ERp57 in the peptide loading copmlex?

A

may have a role in breaking and re-forming disufide Ia chain during peptide loading and forming a stable bond with tapasin

61
Q

Waht is peptide editing?

A

mediates the exhchange of low-affinity peptides bound to the MHC molecule for peptideds with a higher affinity

62
Q

What transports peptides that aren’t bound to MHC back into the cytosol?

A

Sec61

63
Q

What is the function of endoplasmic-reticulum associated degradation (ERAD)

A

reocgnises and delivers misfolded proteins to a retrotranslocation complex which unfolds and transloactes the protesin into the cytosol

64
Q

What do dendritic cells that are capable of cross presentation express?

A

the transcription factor BATF3 and chemokine receptor XCR1

65
Q

What do dendritic cells capable of cross presentation express on their surface in the lymph nodes?

A

CD103- aE integrin

66
Q

Whata re the 2 possible pathways for cross presentation?

A

translocation of ingested proteins from the phagolysosome into the cytosol for degradation by the proteasome etc; or direct transport of antigens into a vesicular loading compartment (without going into the cytosol) where peptides can bind to mature MHC moelcules

67
Q

What is the function of MHC-II presentation in dendritic cells vs macrophages and B cells?

A

dendritic cells want to activate CD4 cells whilst B cells and macropahges want various forms of help from CD4

68
Q

What is foudn in the early endosomes ?

A

neutral pH with inactive endosomal proteases

69
Q

Why do TAP-negative cells express very little surface MHC?

A

inherent instability of empty MHC-I molecules, without peptide binding to form a transport competent molecule

70
Q

What happens in tapasin negative cells?

A

have less MHC on their surface and lower affinity and therefore less stable surface MHC-I molecules

71
Q

What is the function glucosidases I and II in MHCI synteshsis?

A

trims the N-linked glycan to a single terminal glucose residue that allows heavy chain interactions with other proteins

72
Q

What happens to MHCI molecules with suboptimal peptides?

A

UGT1 regucosylates that heavy chain glycan on MHCI allowing reentry of hte MHC-I into the PLC and exchange fro high affinity peptides

73
Q

What are defective ribosomal productions?

A

peptides which are improperly spliced; folded

74
Q

Where do proteins for the proteasome come from?

A

native proteins and exogenous protein (via retro-translocation) as well as DRiPs (from both cellular and viral sources)

75
Q

What happens once MHC-I is dissociated from taapsin?

A

glucosidase II reomves the glucose residue from MHC-I

76
Q

What is the timer that leads to irreverisble dissociation of the MHC-I from the PLC?

A

enzymatic removal of mannose residues from the N-terminal glycan which mean UGT1 cannot regluocsylate it

77
Q

What can happen in the absence of ERAAP (ERAP1/2 in humans)

A

MHC-I are very unstable and the elongated peptides attached to MHC-I result in such structural differences that the immune system recognises them as foregin and a syndrome similar to histoincompatibility and the ability for wild-type mce to generate antibody responses against the MHC-I complexes with long peptides

78
Q

How are self-proteins bound to MHC-II?

A

process of autophagy- damaged oirganelles and cytosolic proteins are delivered to lysosomes for degradation

79
Q

What increases autophagy in a cell?

A

cellular stresses e.g starvation when the cell catabolises intracellular proteins to obtain energty

80
Q

What is microautophagy?

A

cytosol is continously internalised into the vesicular system by lysosomal invagination

81
Q

What is macroautophagy?

A

a double membraned autophagosome engulfs cytosol and fuses with lysosomes

82
Q

what process of sutophagy is induced in cellular stress?

A

macroautophagy

83
Q

When the MHC-II is in the ER what prevents it from binding all the peptides present there?

A

it is bound to MHC-II associated invariant chain (CD74)

84
Q

What is invariant chain CD74?

A

a trimeric glycoprotein where its amino temrinus resides in the cytosol and its carboxy terminus resides in the ER

85
Q

What are hte functions of the I chain fro MHC-II?

A

promotes MHC-II ab folding; protects the MHC-II binding groove and direct MHC to endosomal comprtments for ligand capture

86
Q

What does each invariant chain use to bind noncovalently to an MHC class II a:b heterodimer?

A

CLIP

87
Q

What is the trimeric invariant complex with MHC II molecules assocaited with?

A

calnexin

88
Q

What does disassociated with calnexin require?

A

the formation of a nonamer- 3 invariant chains; 3 MHC alpha units and 3 MHC beta chains

89
Q

What happens once the nonamer is transported to endosomes?

A

the invariant chain is cleaved by proteases to LIP22 and then LIP10 , then just CLIP in the binding groove

90
Q

What is the final cleavage removing hte invariant chain from MHC-II leaving only CLIP carried out by in most cells?

A

cathepsin S

91
Q

What binds to the MHC-class II molecules releasing CLIP?

A

HLA-DM

92
Q

What other function apart fomr the removal of CLIP does HLA-DM play?

A

peptide editing similar to tapasin in MHC-I

93
Q

Where does MHC-II antigen binding take palce?

A

late endosome

94
Q

Where do complexes in the late endosomes come from?

A

from ER via the trans-golgi network or by recycling from the cell surface( some MHC are first transported to cell surface and reinternalised into endosomes)

95
Q

What prevents the removal of CLIP from MHC-II?

A

HLA-DO- inihibts HLA-DM

96
Q

What hpapens to MHC-II molecules which don’t bind peptide after dissociationg from CLIP?

A

unstable in acidic pH after fusion with lsysomes and are degraded

97
Q

What is the function of peptide editing?

A

ensure taht pMHC II complexes displayed on the surface of hte APC are stable to survive long enough to simtulate the appropriate CD4 clel

98
Q

What happens when MHC class I moelcules at the cell surface lose their peptide?

A

conformation changes; b2 microglobulin dissociates and the alpha chain is internalised and degraded

99
Q

What stops antigen processing in dendritic cells after their acitvation?

A

reduced expression of MARCH-1 E3 ligase- increases the lifetime of pMHC complexes on the cell surface

100
Q

What is hte function of MARCH-1?

A

ubiquinates the cytoplasmic tail of MHC-II molecules leading to their degradation in lysosomes

101
Q

How do early endosomes mature into late endosomes?

A

increased luminal acidification and fusion with TGN-derived vesicles delivering enzymes that promote antigen denaturation and proteolysis

102
Q

What is the function of calnexin in MHC I processing?

A

helps initial folding

103
Q

what is hte function of calrexin in MHC-I processing?

A

helps further folding and association of b2 microglobulin and association of Erp57 and tapasin

104
Q

Why does each individual express only a limited number of different MHC molecules in contrast to the large population diversity?

A

represents a trade-off between maximising detection of foreign antigens and minimising loss of T cell clones during self tolerance induction in the thymus

105
Q

What determines the peptide preferences of MHC alleles

A

Peptide preferences are dependent on the amino acids polymorphisms comprising the anchor pockets, which are related to the various alleles of MHC.

Basic Immunology- Module 1 (31 decks)

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