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IMED2001 > Antigen Capture and Presentation to Lymphocytes > Flashcards

Antigen Capture and Presentation to Lymphocytes Flashcards

1
Q

What are the barriers to induction of an immune response by antigens?

A

Low frequency of naive lymphocytes specific for any one antigen.

Different types of adaptive responses required for different types of microbes

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2
Q

What does MHC do?

A

Majority of peptide antigens are recognized

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3
Q

What is MHC restriction?

A

Every individual’s CD4 and CD8 cells can see peptides only when bound to one’s own MHC molecules

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4
Q

What are APCs?

A

Antigen Presenting Cells are cells that capture and display microbial antigens for recognition by T lymphocytes.

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5
Q

What do naive T lymphocytes need to see?

A

Protein antigens as presented by dendritic cells. (DCs are the most effective APCs at initiating clonal expansion and differentiation of T cells into effector cells)

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6
Q

What must differentiated effector T cells do to activate effector functions of T cells?

A

They need to see the antigen again

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7
Q

How do lymphocytes respond to so many antigens hitting body surfaces at the same time?

A

APCs are located in epithelial membranes which are the interaction between internal environment and outside world.

APCs go to lymph nodes and present antigens to lymphocytes there.

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8
Q

A type of dendritic cell that is also an antigen presenting cell:

A

Langerhan cells

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9
Q

What are the types of dendritic cells?

A

Classical dendritic cells (eg langerhan cells)

Plasmocytoid dendritic cells

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10
Q

What do classical dendritic cells do?

A

Induction of T cell responses against most antigens

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11
Q

What do plasmocytoid dendritic cells do?

A

Antiviral innate immunity and induction of T cell responses against viruses

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12
Q

What are the major cytokines produced in classical dendritic cells?

A

TNF, IL-6, IL-12, IL-23

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13
Q

What are the major cytokines produced by plasmacytoid dendritic cells?

A

Type I interferons

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14
Q

Where are classical dendritic cells located?

A

Tissues

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15
Q

Where are plasmacytoid dendritic cells located?

A

Blood and tissue

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16
Q

Where are classical dendritic cells located?

A

Tissue

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17
Q

What do immature APCs do to capture protein antigens?

A

Immature dendritic cells express many receptors on their cell surface (eg lectin receptors).

1) 2 triggers activate DCs:

Microbes enter cell via receptor-mediated endocytosis or pinocytosis.

Microbial products stimulate TLRs enhancing TNF and IL-1

2) DC is activated and there are changes in phenotype, migration, and function. (DCs lose adhesiveness for epithelia, Express chemokine receptor CCR7, and migrate to chemokines produced by lymphatic endothelium and stromal cells in T cell zones of lymph nodes)
3) During migration to lymph nodes DCs mature into APCs that are capable of stimulating T lymphocytes in increased synthesis and stable expression of MHC and co-stimulators required for T-cell response.

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18
Q

What happens when DCs are activated by binding of microbes to receptors on surface and TLRs?

A

DCs lose adhesiveness for epithelia

They express CCR7 chemokine receptor

They migrate to the chemokines produced by lymphatic endothelium and stromal cells in T cell zones of lymph nodes.

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19
Q

What happens when DCs are activated by binding of microbes to receptors on surface and TLRs?

A

DCs lose adhesiveness for epithelia

They express CCR7 chemokine receptor

They migrate to the chemokines produced by lymphatic endothelium and stromal cells in T cell zones of lymph nodes.

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20
Q

What happens to DC on its way to the lymph node?

A

It increases synthesis of cytokines

Stable expression of MHC and co-stimulators required for T cell response

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21
Q

How long does it take for DCs and naive T cells to come together in lymph nodes?

A

Within 12-18 hours of mictobial entry

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22
Q

What kind of response do DCs induce?

A

They are principle inducers of T cell-dependent responses - most potent at activating naive T cells.

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23
Q

What kind of response do macrophages induce?

A

Macrophages are abundant in all tissue and present antigen of microbes they’ve consumed inducing further macrophage response by presenting antigens to effector T cells.

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24
Q

What kind of antigen presentation do B cells do?

A

They ingest protein antigens and display to helper T cells within lymphoid tissues - resulting in development of humoral responses

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25
Q

What is the principle function of dendritic cells?

A

Initiation of T cell response to protein antigens.

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26
Q

What is the principle function of macrophages?

A

Effector phase of cell-mediated immune responses

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27
Q

What is the function of B lymphocytes?

A

Antigen presentation to CD4+ helper T cells in humoral responses (cognate T cell - B cell interactions)

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28
Q

Which non-leucocyte cells express MHCII?

A

Vascular endothelial cells

Thymic epithelial cells

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29
Q

Why do vascular endothelial cells express MHCII?

A

Role in immunity is not established yet

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30
Q

What is the purpose of MHCII in thymic epithelial cells?

A

Role in T-cell maturation and selection

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31
Q

What class of MHC - associated peptides are expressed on all nucleated cells?

A

MHCI

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32
Q

How does a T cell recognize a complex of peptide antigen displayed by an MHC molecule?

A

MHC molecules are expressed on APCs and function to display peptides from protein antigens.

Peptides bind to MHC molecules by anchor residues which attach peptides to pockets in MHC molecules.

T cell receptor recognises some residues of peptide and some (polymorphic) residues of MHC molecules.

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33
Q

What are the important sites of interaction between APC and T cell?

A

APC has MHC on it with peptide being displayed

Direct recognition of self MHC takes place in the polymorphic residues and it isn’t specific to the antigen being presented.

In the middle of the MHC is the peptide being displayed with some parts that come in contact with the T cell receptor. All polymorphic and peptide specific antigens must bind to T cell receptor for a response to occur.

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34
Q

What is the purpose of MHC?

A

It displays peptides from microbial protein antigens to antigen-specific T-lymphocytes.

It is responsible for rejection or acceptance of tissue grafts.

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35
Q

What are human MHC proteins called?

A

Human Leukocyte Antigens (HLAs)

36
Q

What are the classes of loci in the HLA gene?

A

Class I (A, B, C)

Class II (DP, DQ, DR - each consists of at least 2 genes)

Class III (genes that encode molecules other than peptide display molecules, eg complement, cytokines, and proteasome genes)

37
Q

How are the gene loci distributed in the HLA gene?

A

They are separated by long sequences.

38
Q

How are genes expressed in MHC?

A

All alleles are equally dominant.

39
Q

What are the class I genes?

A

HLA-A HLA-B HLA-C (each person gets one from each parent)

40
Q

What are the class II genes?

A

Pair of HLA-DP genes (DPA1 and DBP2 encode alpha and beta chains)

Pair of HLA-DQ genes (DQA1 and DQB1 encoding alpha and beta chains)

1 HLA-DRalpha gene from each parent (DRA1)

1 or 2 HLA-DRbeta genes from each parent (DRB1 & DRB3,4,5)

41
Q

Do all cells express class I molecules?

A

Any cell can express 6 different class I molecules (i.e any nucleated cell)

42
Q

How are MHC genes so polymorphic?

A

HLA alleles in population are estimated to be more than 5000 - ~2500 for HLA-B locus alone..

43
Q

Why do MHC genes need to be polymorphic?

A

Multiple alleles ensure some members of population will always be able to present any particular antigen.

Evolved to ensure that population as whole will be able to deal with diversity of microbes.

This means that not everyone will die to newly encountered or mutated microbe

44
Q

Which cells have Class II molecules?

A

Mainly on DCs, macrophages, and B lymphocytes. Also on thymic epithelial cells and endothelial cells.

45
Q

What is the purpose of class I molecules?

A

Allows CD8+ Cytotoxic T lymphocytes to detect and kill any virus-infected cells.

46
Q

What induces class II molecule expression?

A

Interferon-gamma

47
Q

What response do class II molecules induce?

A

CD4+ helper T lymphocytes which interact with dendritic cells, macrophages, and B lymphocytes

48
Q

What are the important parts of the MHC molecules?

A

Class I MHC:

Contains polymorphic peptide-binding cleft at amino terminal. This cleft has a place for peptides to bind for display to T cells, sides and tops of cleft make contact with T cell receptor.

Immunoglobin binding domains on both sides (both chains) with a disulfide bond creating a rounded structure

C terminal has hydrophobic chains which anchor the protein in the membrane

49
Q

Describe MHCI molecule:

A

Each MHC I molecule contains alpha chain non-covalently bound to beta-microglobulin encoded by gene outside MHC. (beta-microglobulin domain is separate completely from the main protein)

Amino-terminal alpha1 and alpha 2 domains of class I MHC form peptide binding cleft large enough to accommodate peptides that are 8 - 11 amino acids long.

50
Q

What size are peptides presented by APCs?

A

8 - 11 amino acids wide

51
Q

What are the chains of MHCII molecules?

A

alpha chain

beta chain

52
Q

How many residues can class II MHC take?

A

10 - 30 residues

53
Q

How is variation in the peptide-binding cleft maintained?

A

Some polymorphic residues contribute to variations in floor of peptide-binding cleft and ability of different MHC molecules to bind peptides

Other polymorphic residues contribute to variations in tops of clefts and influence recognition by T cells

54
Q

How does MHCII differ from MHCI?

A

MHCII binding site holds peptides of 10 - 30 amino acid lengths, MHCI holds peptides of 8 -11 amino acid length.

MHCII has binding site for CD4+ T cell receptor.

55
Q

How can a single MHC molecule recognize so many antigens that it is presenting?

A

Only 1 - 2 residues are needed to bind to the cleft of a particular MHC molecule. This ability is essential for antigen display function due to large number of antigens

56
Q

What kind of antigens are recognized by MHC molecules?

A

Only protein peptide antigens.

57
Q

What cells can recognize MHC antigens?

A

CD4+ and CD8+ T cells only

58
Q

Where do class I MHC molecules get their peptides?

A

Cytosolic proteins

59
Q

Where do class II MHC molecules get their peptides?

A

From proteins taken up into intracellular vesicles

60
Q

What must happen to MHC for it to be expressed on the surface?

A

A peptide must be bound, once peptides bind to MHC they stay bound for a long time (several days)

61
Q

At any time, quantitiy of self proteins is certain to be greater than microbial antigens. Why are available MHC molecules not constantly occupied by self peptides?

A

New MHC molecules are constantly being synthesised

A single T cell only needs to see peptide displayed by as few as 0.1 - 1% of the 10^5 MHC molecules on surface of APC

Even rare MHC molecules displaying a peptide are enough to initiate an immune response

62
Q

If MHC molecules are constantly displaying self peptides, why do we not develop immune responses to self antigens?

A

T cells specific for self antigens are either killed or inactivated - tolerance

T cells are constantly patrolling the body looking for MHC-associated peptides - if there is an infection only those T cells that recognise microbial peptides will respond.

63
Q

How are antigens processed to present on MHCII?

A

Uptake of protein into vesicles of APC

Processing of internalized proteins in endosomal/lysosomal vesicles

Biosynthesis and transport of class II molecules to endosomes

Association of processed peptides with class II MHC molecules in vesicles

Expression of peptide-MHC complexes on cell surface

Class II complex binds with CD4+ T cells at 2 sites (CD4+ and T-cell receptor)

64
Q

Do proteins that are degraded get broken down into 1 or many peptides?

A

Many

65
Q

How do MHCII filled vesicles not bind to resident amino acids within the same vesicles?

A

They bind to Class II invariant chain Peptides (CLIP)

66
Q

How is CLIP removed from the MHCII molecule?

A

HLA-DM molecule removes clip and facilitates loading of antigen

67
Q

How are class I MHC molecules occupied by self proteins?

A

Cytoplasmic proteins are unfolded, uniquitinated and degraded in proteasomes.

Peptides transported by a transporter associated with antigen processing (TAP) into ER for more trimming.

Class I MHC strategically located to receive peptides transported into ER by TAP

Newly synthesized class I MHC attached to peptide via TAP linker protein (tapasin).

Peptide-class I MHC complex is transported to cell surface and recognized by CD8+ T cells

68
Q

Where does attachment of peptide to newly synthesized class I MHC take place?

A

On ER membrane

69
Q

How does class I MHC attach to the TAP protein?

A

Via a chaperone protein

70
Q

Where does MHCI get attached to an exocytic vesicle?

A

In the golgi apparatus

71
Q

What does the CD8 arm of the CD8 T cell bind to when binding to MHCI?

A

The T cell receptor binds to the displayed peptide and the CD8 arm binds to the invariant chain

72
Q

What are the differences between MHCI and MHCII in both structure and action?

A

MHCII is composed of continuous alpha and beta chain whereas MHCI is composed of alpha chain and a beta2-microglobulin

MHCII is expressed by DCs, Mononuclear phagocytes, B lymphocytes, endothelial cells, thymic epithelium. MHCI in all nucleated cells.

CD4+ helper T cells respond to MHCII whereas CD8+ cytotoxic T cells respond to MHCI (function makes this obvious)

MHCII proteins get their antigens from endosome/lysosome proteins (obtained from extracellular environment mostly), MHCI get proteins from cytososlic proteins synthesized in the cell which enter the cytosol from phagosomes. (Think again of function)

MHCII derives peptides from produce of lysosomal and endosomal protease breakdown. MHCI uses the ubiquitin/proteosome system.

MHCII load peptides in specialized vesicles. MHCI do so in the ER.

73
Q

What is cross-presentation of antigen?

A

Virus infected cell can be consumed by DCs which break down the infected cell AND the viruses it is infected by and then present its peptides on MHCI while simultaneously releasing CD8+ attracting cytokines. In some cases the antigen taken up by this method can present on MHCII and instigate a CD4+ response.

(This can also be done with tumour cells)

74
Q

Why are there 2 separate classes of MHC molecules? (What’s the point of all this?)

A

It allows T cells to respond appropriately to different classes of pathogens in the appropriate way. Intracellular pathogens get the cytotoxic treatment and get killed with their host cells and extracellular pathogens get phagocytosed by the increased activity of the macrophages that are activated by CD4 T lymphocytes which are also activated by Macrophages.

75
Q

What happens when B cell engulfs an extracellular antigen?

A

It results in a CD4 helper response which further results in production of more antibodies

76
Q

What is immunodominance of peptides in regard to MHC molecules?

A

Immunodominant peptides can bind well with MHC molecules because their structure (length + anchor residues) make them most dominant at binding to MHC and so they end up being expressed more often than other peptides

77
Q

What does immunodominance mean for scientists/medical professionals?

A

The enormous polymorphism/variablity seen in people makes it hard for a small number of peptides to be selected for an appropriate vaccine.

Also many people may not express MHC molecules capable of binding to any peptide derived from a particular antigen. (non-responders to that particular antigens)

78
Q

What is required to trigger an immune response in addition to APC antigen display and binding to TCR?

A

We need a cytokine response and binding of other signalling proteins. Co stimulation with B7 (APC) and CD28 (on T cell)

79
Q

What is another response to IL-2 production?

A

Proliferation and production of memory T cells

80
Q

What kind of antigen conformation do B cells recognize?

A

They recognize antigens in their native conformation with no requirement for antigen presentation

81
Q

What do follicular DCs do?

A

They display antigens to activated B cells.

82
Q

How do follicular DCs display their antigens?

A

They use antibody receptors to bind antigen-antibody complexes and receptors for complement proteins to bind antigens with these complement proteins attached.

83
Q

What does Follicular DC action do to B cell response?

A

Selects B cells that bind antigens with high affinity

84
Q

What are NK-T cells?

A

Distinct cells from NK and T cells. They are specific for lipids displayed by class I-like CD1 molecules

85
Q

What are yσ T cells?

A

Cells that recognize a wide variety of molecules of which some are displayed by class I like molecules. and others apparently requiring no specific processing or display.

86
Q

How are yσT and NK-T cell functions understood?

A

Not very well

IMED2001 (44 decks)

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