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YEAR 2 S2 IMMUNO > Theme 3- 3b (Antigens and Antigen receptors pt 2 ) > Flashcards

Theme 3- 3b (Antigens and Antigen receptors pt 2 ) Flashcards

1
Q

what are the antigen presenting molecules used by T cells

what are their classes

A 
MHC class I 
MHC class II
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2
Q

what is a paratope

A

antigen binding site

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3
Q

what can T cells bind to

A

the bind LINEAR ARRAYS of approx 9 aa via TCR

  • NOT native Ag
  • Ag is broken down to primary structure (PROCESSED) and PRESENTED to the T cell by molecules on the surface of Ag presenting cells (eg macrophages and dendritic cells)
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4
Q

what are the similarities between the BCR and TCR

A
  • TCRs are similar to Fab fragment of B cell
  • both TCR and BCR are composed of: 2 different peptide chains, variable region for binding antigen, constant regions, hinge regions
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5
Q

what are the differences between the BCR and TCR

A

TCR only has ONE antigen binding site

BCR has TWO

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6
Q

what are the TWO TYPES of TCR

A

αβ and γδ - with distinct functions

- which type is dependant on which genes encode the protein

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7
Q

describe the structure of TCR

A

VARIABLE REGION: made of of the V domains (Vα/Vβ or Vγ/Vδ) for antigen binding

CONSTANT REGION: made up of the C domains (Cα/Cβ or Cγ/Cδ)

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8
Q

do TCRs have a non membrane bound secretion

A

no, they are always membrane bound

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9
Q

how many antigen binding sites do TCRs have

A

ONE

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10
Q

does TCR have signalling molecules?

A

no- O it uses CD3 (an accessory molecule) instead

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11
Q

what is the structure of CD3

look at slide 8 for diagram

A

consists of 6 polypeptides:
ζζ, γε and εδ dimers
- ζ chains have 3 ITAMs
- γ, ε and δ have extracellular Ig folds and one ITAM apiece

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12
Q

TCRs can either be CD… or CD…?

what does this give rise to

A

CD4 or CD8

  • CD4 or CD8 give ANOTHER WAY of TCR BINDING to the MHC
  • this gives some SELECTIVITY
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13
Q

what are the TCR and CD3 held together by

A

electrostatic interactions, forming a compact structure in the T cell surface

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14
Q

what does each T cell have multiple copies of

where is this randomly generated

A

MULTIPLE copies of a SINGLE variant of the TCR, randomly generated in the THYMUS

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15
Q

describe T cell development

A
  • THYMOCYTES enter the thymus not expressing the TCR or co-receptors (CD4/CD8)
  • REARRANGEMENT of the DVJ segments of genes encoding α and β chains
  • gives each cell a UNIQUE TCR to recognise an epitope
  • if a FUNCTIONAL TCR is not formed (non-productive rearrangement), the T cell DIES by apoptosis
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16
Q

what % of thymocytes that enter the thymus actually become T cells

A

5% (rest die by apoptosis)

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17
Q

antibodies deal best antigens where

give examples

A

antigens that are outside the cell (eg bacteria outside cells/viruses outside of cells)

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18
Q

T cells are v good at attacking what type of antigen

give examples

A

antigens WITHIN CELLS so we want to KILL the cell (endogenous antigens)
eg virally infected cells/tumour cells

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19
Q

what do MOST T cells recognise

A

ONLY peptides

- T cells are specfic for AMINO ACID sequences of peptides

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20
Q

what has to occur for T cells to recognise and respond to FOREIGN peptide antigens

A

antigen has to be presented by MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

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21
Q

CD8 class T cells recognise what type of MHC class

A

MHC class I

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22
Q

CD4 class T cells recognise what type of MHC class

A

MHC class II

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23
Q

what is the purpose of the CD4/CD8 molecules

A

Whilst the TCR recognises and binds the peptide/MHC molecule complex, the CD4 and CD8 molecules also interact with and bind the MHC molecule ensuring stability of the ‘immunological synapse’

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24
Q

in T cell antigen recognition, what is the epitope of the antigen comprised of

A

some aa from the PRESENTED PEPTIDE

also SOME PARTS of the MHC

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25
Q

how are T cells activated

A

1) VARIABLE regions of the TCR αβ chains interact with the peptide in the MHC
2) EPITOPE and PARATOPE must ‘fit’ together
3) after binding of MHC-peptide on the APC with the TCR, either CD4 or CD8 join the complex
4) cellular KINASES and the ITAMs of CD3 initiate T cell activation

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26
Q

how do we ensure T cells are only activated by an antigen

A

CO-STIMULATORY molecules

  • CD28 on the T cell and CD80/86 on APC have to interact
  • CD80/86 is NOT PRESENT unless it has been activated by INNATE immunity
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27
Q

how many types of receptor does each B or T cell express

A

ONE receptor that is specific for ONE antigen

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28
Q

how many BCR (Ig) are there

A

5x10^13

but this is even higher bc of somatic hypermutation/ affinity maturation

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29
Q

how many TCR are there

A

1x10^18

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30
Q

what is clonal proliferation
when does it occur
what does it produce

A

when BCR or antigen or TCR are activated, they undergo clonal proliferation:
the activated cell proliferates O MILLIONS of the cell that can recognise the antigen
- produces TWO TYPES OF CELL:
- EFFECTOR CELLS (aid in antigen/pathogen removal)
- MEMORY CELL (aid in secondary immune responses)

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31
Q

what is a POLYCLONAL response

A
  • pathogens may have MANY antigens each having SEVERAL EPITOPES: proteins, carbohydrates, lipids, metabolites
  • POLYCLONAL response: many clones of B and T cells will expand as they recognise the different antigens and/or different epitopes within them
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32
Q

what is antigen processing

A

how complex antigens/proteins are BROKEN down into peptides and loaded into molecules for PRESENTATION to T cells

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33
Q

MHC is encoded by what genes

A

HLA genes

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34
Q

what are the 4 main groups of HLA genes

A
  • HLA-A, HLA-B & HLA-C region genes (are for MHC CLASS I)
  • HLA-D [actually called HLA-DP, HLA-DQ and HLA-DR] (are for MHC CLASS II)
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35
Q

what does HLA stand for

A

human leukocyte antigens

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36
Q

describe MHC class I

A
  • on ALL nucleated cells and platelets
  • targets for GRAFT REJECTION
  • involved in Ag recognition of VIRALLY infected cells
  • Present peptides to CD8+ T cells (cytotoxic T cells) so essential in viral infections or recognition of altered self (such as tumour cells)
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37
Q

what is the structure of MHC class I

A
  • a1 and a2 domains consist of 4 b strands and an a helix

- these form a groove or cleft which is the Ag-binding site of the molecule

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38
Q 
where is class I MHC found 
give examples
A

on antigen presenting cells (APCs)

eg dendritic cells, macrophages, B cells

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39
Q

what is the role of class II MHC

which structure forms the peptide binding site

A
  • Ag presentation to T cells (CD4+ helper T cells), where the T cell can be activated an dundergo proliferation ad cytokine secretion
  • a1 and b1 domains form peptide binding site like Class I
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40
Q 
what is a size difference in MHC class I and II 
what is the difference in aa number that each class can bind
A

MHC class I has slightly smaller groove

  • 8-10 aa peptides can bind to MHC class I
  • 13-18 aa peptides can bind to MHC class II
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41
Q

why is there a difference in size between MHC class I and II

A

MHC class II is comprised of more chains O has the flexibility to accomodate larger peptides

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42
Q

why does each MHC molecule display ONE peptide at a time

A

each T cell responds to a SINGLE peptide bound to an MHC molecule

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43
Q

why do MHC molecules have low affinity and broad specificty

A

so many different peptides can bind to the same MHC molecule

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44
Q

why do MHC molecules acquire peptides during intracellular assembly

A

both class I and II MHC molecules display peptides from DIFFERENT cellular compartments

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45
Q

why do MHC molecules have a very slow off-rate (once peptides are bound they stay there for a DAYS -long time)

A

to allow the bound peptide to be there long enough to be LOCATED by a T cell

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46
Q

why is it important that for an MHC to be stable a peptide bound is req

A

MHC without peptides are very unstable O taken back into cell and endocytosed
- only MH that are displaying peptides are expressed for recognition by T cells

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47
Q

what do MHC molecules ONLY bind to

A

peptides

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48
Q

how can MHC interact with haptens

A

haptens (eg causing response to chemicals) can be combined with a peptide to cause an IMMUNE RESPONSE

49
Q

what is class I MHC formed of

A

one chain (a1, a2, a3 domains) and interacts with CD8+ T cells. Also has b2-macroglobulin

50
Q

what is class II MHC formed of

A

two chains (a1, a2 domains on one b1, b2 on the other) and interacts with CD4+ T cells

51
Q

where are dendritic cells located

A
  • skin
  • GI and resp tracts
  • parenchyma
52
Q

where are Langerhans cells located

A

they are dendritic cells in the epidermis (skin)

53
Q

what happens if a Langerhans cell is activated

A
  • if bacteria is present they present antigen
  • they detach from surrounding tissue and MIGRATE via LYMPHATIC vessels to LYMPH NODE
  • THE LYMPH NODE captures antigen
  • this is where the antigens are presented and they may encounter a T cell
54
Q

describe the general capture and presentation of protein antigens by DCs

A
  1. Antigen is processed at the site of infection by dendritic cells (DCs)
  2. The DCs become migratory; they detach and enter the lymphatic vessels (soluble antigen can also enter lymphatics)
  3. These vessels empty into lymph nodes in the parcortex area bringing the DCs (and soluble antigens)
  4. The DCs then become positioned on the fibroblastic reticular cell (FRC) network (soluble antigens can be processed by other APCs here)
  5. Here they are scanned by naïve CD4 or CD8 T cells
55
Q

dendritic cells link what

A

innate and adaptive immunity

  • Innate – phagocytosis of antigens, production of cytokines due to PAMPs
  • Adaptive – following on, antigens can be presented on MHC and the cytokines help activate the T cells
56
Q

which MHC is endogenous, which is exogenous

A

endogenous (MHC I) and exogenous (MHC II)

57
Q 
how are antigens presented in the endogenous pathway (MHC class I)
ie how does the peptide end up in the MHC
A
  • peptide antigens are from WITHIN cell
  • proteins are PROCESSED by proteasome into SMALL peptides
  • TRANSLOCATED to ER lumen by heterodimeric TAP (transporter associated with antigen processing)
  • they are loaded into MHC class I here
  • ANTIGEN:MHC I complex is TRANSPORTED to cell memb
58
Q 
how are antigens presented in the exogenous pathway (MHC class II) 
ie how does the peptide end up in the MHC
A
  • antigens are from OUTSIDE of the cell
  • antigens are ENGULFED into ENDOCYTIC compartments and DEGRADED to peptides
  • they are loaded into MHC class II in CYTOPLASMIC vesicles
  • antigen:MHC II complexes are transported to CELL MEM
59
Q

MHC I is associated with what type of Tcell

A

CD8 cytotoxic T cells

can remember this as I is drawn similarly to T

60
Q

MHC II is associated with what type of Tcell

A

CD4 T Helper cells

61
Q

in detail explain the steps before peptides bind to MHC I

slide 40 for diagram

A

1) MHC class I alpha chain associates with the chaperone protein Calnexin and ERp57
2) Β2 macroglobulin binding displaces Calnexin
3) Calreticulin and Tapasin (TAP associated protein) also bind, creating a “peptide loading complex”
4) Peptides (that may have been further processed by ERAP so that they are 8-10 amino acids in length) can then bind, stabilising the complex so that it can then be transported to the cell surface

62
Q

in detail explain the steps before peptides bind to MHC II

slide 41 for diagram

A

1) MHC II and invariant chain (Ii) made in ER, then transported through Golgi to a vacuole that fuses with late endosomes → MHC class II enriched compartment (MIIC
2) Antigen enters via receptor-mediated endocytosis, via early endosome until it forms the MIIC late endosome
3) Ii degrades leaving CLIP protein, then DM facilitates the replacement of CLIP with peptide 13-18 amino acids in length
4) Finally complex is transported to the cell surface

63
Q

what are the components of a stable peptide-MHC complex made in MHC class I

A

polymorphic alpha chain, beta2 microglobulin, peptide

64
Q

what are the components of a stable peptide-MHC complex made in MHC class II

A

polymorphi alpha and beta chains, peptide

65
Q

what are the types of APCs for MHC class I

A

all nucleated cells and platelets

66
Q

what are the types of APCs for MHC class II

A
  • dendritic cells
  • mononucleat phagocytes
  • B lymphocytes
  • endotheial cells
  • thymic epithelium
67
Q

what are the sources of protein antigens for MHC class I

A

cytosolic proteins (mostly synthesised in cell)

68
Q

what are the sources of protein antigens for MHC class II

A

endosomal/lysosomal proteins (mostly internalised from extracellular env)

69
Q

what is the site of peptide loading into MHC I

A

ER

70
Q

what is the site of peptide loading into MHC II

A

specialised vesicular compartment

71
Q

which molecules are involved in the transport of peptides and loading of MHC I molecules

A

TAP

72
Q

which molecules are involved in the transport of peptides and loading of MHC II molecules

A

invariant chain, DM

73
Q

what is the purpose of MHC class I (endogenous) presentation

A
  • presentation to cytotoxic T cells

- kill virally infected cells/Tumour cells/Intracellular pathogens

74
Q

what is the purpose of MHC class II (exogenous) presentation

A
  • presentation to T helper cells

- kill external pathogens (which need to be killed by ANTIBODIES, most of which are made with T cell help)

75
Q

what are the classical T cells

which are the non classical t cells

A

classical: αβ T cells
non: γδ T cells

76
Q

what % of circulating T cells are classical

A

95-99% are αβ

77
Q

where are non classical T cells found

give an example

A

epithelial rich tissues (eg gut)

mucosa (50% of T cells here are non cassical)

78
Q

what is the difference between classical and non classical T cells

A

non classical have different TCR: they have γδ instead

79
Q

what is the diversity of non classical T cells like

A

LESS diversity, they bind to non-conventional antigens

80
Q

which group has higher levels of non classical T cells

A

foetus

81
Q

how do γδ T cells recognise antigen differently

A

they recognise antigen presented in CD1 rather than MHC

82
Q

what do γδ T cells recognise/load

A
  • they can load LIPIDS into the groove of CD1 as opposed to peptides
83
Q

what is the purpose of γδ T cells

A

not entirely clear, but they RECOGNISE LIPIDS, PATHOGENS (such as M.tuberculosis) and PATHOGENIC TOXINS, CELLULAR STRESS MARKERS

84
Q

what makes superantigens

A

some bacteria and viruses

85
Q

what are superantigens

A

proteins that BYPASS NORMAL ANTIGEN RECOGNITION and BIND:

  • non-variable sequences of TCR variable regions
  • non-polymorphic sequences of MHCII α-chain
  • they can activate 5-20% of T helper cells
  • they are effective at v low conc ( ~ 10^-9M)
86
Q

are superantigens processed by APCs?

A

no

they bind in their native state

87
Q

describe the structure of an alpha beta TCR

A
  • one chain has EXTRACELLULAR Ig domain which is CONSTANT region
  • there is a VARIABLE region at the end
  • transmembrane region
  • very short cytoplasmic region
  • beta chain has v similar structure
88
Q

how does the memb bound alpha and beta chains of TCR communicate to T cell that it has bound peptide

A

using CD3 molecule

89
Q

what is the structure of the CD3 molecule

A
  • comprised of 6 chains: gamma, delta, 2x epsilon, 2x zeta
  • have Ig domain externally
  • have transmembrane region
  • and have LONG CYTOPLASMIC TAIL which have ITAMS
90
Q

what happens at ITAMs

A

phosphorylation which signals to cell

91
Q

what is the structure of the gamma and delta chains of the CD3 molecule

A
  • have Ig domain externally
  • have transmembrane region
  • and have LONG CYTOPLASMIC TAIL which have ITAMS
92
Q

what is the structure of the 2x epsilon chains on the CD3 molecule

A
  • have Ig domain externally
  • have transmembrane region
  • and have LONG CYTOPLASMIC TAIL which have ITAMS
93
Q

when a peptide binds to the variable region on the TCR what happens to the CD3molecules

A

all the cytosolic parts of the TCR are carried by LIPID RAFTS, and they CLUSTER TOGETHER
- after clustering, the ITAMs will be PHOSPHORYLATED and signal transduction will occur

94
Q

what are the similarities between BCR and TCR

A

1) same Ig FAMILY
2) both have CONSTANT and VARIABLE regions
3) both use the VARIABLE region to bind native antigen (BCR) or peptides (TCR)
4) both have transmembrane domains
5) both have v short cytoplasmic domains which are not able to signal by themselves O rely

95
Q

how is TCR and BCR different

A

1) BCR has MORE extracellular domains
2) one TCR can only bind ONE peptide, whereas BCR can bind up to TWO antigens
3) to transduce signals to the cell, the BCR uses CD79 alpha and beta and TCR uses gamma, delta, 2x epsilon and 2x zeta chains

96
Q

how many chains does MHC I have

A

one

97
Q

what family of molecules does MHC belong to

A

Ig family O have Ig like domains

98
Q

what is the structure of domain 2 on MHC class I

A

made of BETA PLEATED sheets, and then forms an ALPHA HELIX

99
Q

what is the structure of domain 3 on MHC class I

A

forms BETA PLEATED sheets (which interact w/ beta pleated sheet s from domain 2) and then another ALPHA HELIX forms on top

100
Q

what stabilises the peptide once it is bound in the groove of MHC class I binding site

A

BETA 2 MICROGLOBULIN

101
Q

why is MHC class I expressed on all nucleated cells

A

as all cells can be infected (eg by virus/ intraceullular bacteria/tumour cell)

102
Q

how are viral particles for eg moved to the MHC class I on cell surface

A
  • they are broken down to peptides by the proteasome into peptides
  • the peptides enter the ER
  • ER is where MHC class I is also being produced
  • then peptides are moved to cell surface
103
Q

which cells express MHC class II

A

antigen presenting cells (mainly macrophages and dendritic cells, but B CELLS can also act as APCs)

104
Q

how many chains is MHC class II comprised of

A

TWO chains

105
Q

what is domain one on MHC class II chains

A

BETA PLEATED SHEET and an ALPHA HELIX

106
Q

what is domain two on MHC class II

A

Ig like domain

107
Q

how do the 2 chains on MHC class II interact to form the peptide binding site

A

the two beta pleated sheets interact forming the peptide binding groove

108
Q

what is the tightness of the alpha helices like in MHC class II, what does this mean for the peptide that binds?

A

the alpha helicies are LESS TIGHT

O a slightly longer peptide can fit

109
Q

what is a difference in stability once the peptide/antigen has bound in MHC I compared with MHC II

A

MHC II structure is mroe stable O doesn’t req the beta 2 microglobulin sturcture to stabilise

110
Q

how is the peptide laoded onto the MHC II

A

the MHC II presenting cells are APCs, which are PHAGOCYTIC

- they PHAGOCYTOSE exogenous material where they bring them into the PHAGOLYSOSOME and they are converted to peptides

111
Q

dendritic cells and macrophages produce which type of MHC

A

BOTH MHC I and MHC II
MHC I as they are NUCLEATED O prod MHC I
but they are professional APCs O also display MHC II

112
Q

as both MHC class I and II are being made in the ER, why is MHC II not loaded with the SAME peptides as the MHC I

A

as MHC II is being made in the ER, the INVARIANT CHAIN comes and sits ON TOP of the PEPTIDE BINDING GROOVE thus BLOCKING the binding groove of the MHC II molecules so they aren’t loaded with ENDOGENOUS peptides

113
Q

after synthesis in the ER what happens to MHC II

A
  • translocated THROUGH the cell to MEET phagolysosome /endosome
  • invariant chain is degraded
  • the EXOGENOUS peptides are loaded into the peptide binding groove
  • then the loaded MHC II can be transported to the surface of cell to present peptide to CD4+ helper T cells
114
Q

why is MHC considered to be human leukocyte ANTIGENS

A

any molecule that presents foriegn peptides/antigens needs to be able to recognise a WIDE variety of antigens O not all individuals have exactly the same MHC molecules

115
Q

what does histocompatibility mean

why is this important in transplants

A

‘histo’= tissue
‘compatibility’ = matching
- we need to ensure the MHC class I (esp) needs to be compatible in donor and recipient

116
Q

which cell is very important in mounting an immune response to eg transplant
why is MHC considered to be HUMAN LEUKOCYTE ANTIGEN

A

MHC I

  • a donors MHC I could be slightly different to the recipients
  • as MHC I is expressed on EVERY RECIPIENT CELL, all these cells could be part of an immune repsonse against the transplant
117
Q

what causes variation in MHC complexes

A

as a species variation is important so we are not wiped out by a pandemic by presenting slightly different peptides and antigens

118
Q 
when is CLIP formed in MHC class II pathway
what removes CLIP
A

CLIP IS formed after invariant chain (Ii) is processed following the fusion of the MHC class II enriched compartment (MIIC) with late endosomes.

It IS then removed by HLA-DM

YEAR 2 S2 IMMUNO (14 decks)

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