8 - Antigen Presentation to T cells Flashcards

1
Q

Routes of antigen entry

A
  • Skin and gastrointestinal, and respiratory tracts
  • Antigens are captured by dendritic cells and transported to regional lymph nodes
  • Antigens that enter the bloodstream are captured by APCs in the spleen
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2
Q

How are peptides shown to T cells

A

By APCs (Dendritic cells, macrophages, and B cells)

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3
Q

Naive T cell activation

A

Clonal expansion and differentiation into effector T cells

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4
Q

Effector T cell activation

A
  • Activation of macrophages (cell mediated immunity)
  • B cell activation and antibody production (humoral immunity)
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5
Q

How do T cells recognise peptide antigen

A

In context of MHC molecules

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6
Q

Antigen processing

A

Conversion of native proteins into MHC associated peptides

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7
Q

Antigen presentation

A

Display of peptide at cell surface by MHC molecules

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8
Q

What are the 2 different intracellular compartments that MHC class 1 and 2 molecules deliver peptides to the cell surface by

A

The cytosol or the vesicular system

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9
Q

Antigen uptake in Class 1 MHC pathway

A

Cytosolic protein (endogenous pathway - used for viruses and intraceullar bacteria)

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10
Q

Antigen uptake in Class 2 MHC pathway

A

Endocytosis of extracellular protein (exogenous pathway - protein comes from outside cell)

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11
Q

Class 1 MHC pathway

A

Protein antigens in the cytosol are processed by proteasomes, and peptides are transported into the ER, where they bind to class I MHC molecules

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12
Q

Class 2 MHC pathway

A

Protein antigens that are degraded in lysosomes bind to class II MHC molecules

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13
Q

Dendritic cells antigen capture and presentation

A
  • Immature dendritic cells in the skin (Langerhans cells) or dermis (dDCs) capture antigens that enter through the epidermis and transport the antigens to regional lymph nodes.
  • During this migration, the dendritic cells mature and become efficient APCs
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14
Q

Function of tissue resident resting DC in T cell activation

A

Antigen capture

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15
Q

Function of activated DC in T cell activation

A

Antigen presentation to T cells

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16
Q

Expression of Fc receptors, mannose receptors on tissue resident resting DCs

A

Very high

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17
Q

Expression of Fc receptors, mannose receptors on activated DCs

A

Low

18
Q

Expression of molecules involved in T cell activation (homing): B7, ICAM-1, IL-12 on tissue resident resting DCs

A

Low

19
Q

Expression of molecules involved in T cell activation (homing): B7, ICAM-1, IL-12 on activated DCs

A

Very high

20
Q

Half life of class 2 MHC molecules on tissue resident resting DCs

A

Short (~10 hours)

21
Q

Half life of class 2 MHC molecules on activated DCs

A

Long (>100 hours)

22
Q

Conventional (or classical) DCs (cDCs)

A
  • Present in most epithelia that interface with the external environment, such as the skin, intestinal and respiratory tracts, and in tissues,
  • Capture antigens and transports them to secondary lymphoid organs and present antigen to naive CD4 + and CD8 + T cells.
23
Q

Two groups of cDCs

A
  • Type 1 (cDC1): efficient at transferring ingested antigens from vesicles into the cytosol (Important cross-presentation step)
  • Type 2 (cDC2): The major DC subset that presents captured antigens to CD4 + T cells (the subset that is most important for initiating response)
24
Q

Plasmacytoid DCs (pDC)

A
  • Major source of type I IFN and are essential for innate immune responses to viruses.
  • Also may capture antigens in the blood and transport them to the spleen.
25
Q

Monocyte derived DCs (moDC)

A

Can be induced to develop from monocytes under inflammatory conditions

26
Q

Langerhans cells

A
  • Earliest DCs identified
  • Function similar to that of cDC2
  • Develop early in life
27
Q

Examples of antigen that use MHC class 1 pathways

A

Antigens from cytoplasmic cellular proteins, from intracellular pathogens, or from tumour proteins

28
Q

Transport of peptides from cytosol to ER in MHC class 1 pathway

A
  • The proteosome digests proteins to produce peptides which then enter the ER to associate with MHC-I molecules
  • TAP1 (transporter associated with antigen processing) and TAP2 proteins translocate peptides 8-16 aa long into ER lumen
  • Some additional enzyme-mediated trimming occurs in ER
29
Q

What happens to peptides too long to bind to MHC 1 molecules

A

Can be trimmed with an aminopeptidase, endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP)

30
Q

MHC-1 expression

A
  • Newly synthesised MHC-1 α chains assemble in the ER with membrane bound calnexin
  • Binding of β2 microglobulin dissociates calnexin
  • The partly folded MHC molecule then binds to TAP by interacting with tapasin
  • Chaperone molecules bind and stabilize the complex
  • MHC-I molecule is retained within ER until it is released by binding with a peptide (this completes the folding of the MHC molecule)
  • Once a peptide has bound to the MHC, the peptide/MHC complex leaves the ER and is transported through the Golgi apparatus to the cell
    surface
31
Q

Defective ribosomal proteins

A
  • DRiPs and proteins marled (ubiquitinated) for destruction are transported into ER by TAP
32
Q

Acidified endocytic vesicles in MHC class 2 pathway

A
  • Antigen is taken up from extracellular space into intracellular vesicles
  • In early endosomes of neutral pH, endosomal proteases are inactive
  • Acidification of vesicles activates proteases to degrade antigen into peptide fragments
  • Vesicles containing peptide fuse with vesicles containing MHC class 2 molecules
33
Q

MHC-2

A
  • MHC-II ⍺ and β chains are found in ER complexed to the invariant chain Ii polypeptide
  • The Ii is cleaved to small fragments one of which, the Class II-associated invariant peptide, CLIP is located in the groove of the MHC-II molecule until replaced by peptide destined for presentation
  • The MHC ⍺β/Ii complex is transported through the Golgi to an endosomalc ompartment (MHC Class II compartment MIIC)
34
Q

Function of invariant chain li

A

Binds to newly synthesised MHC-II and blocks binding of peptides and misfolded proteins found in ER and
during transport of MHC-II

35
Q

Where is li cleaved into CLIP

A

Acidified endosome

36
Q
A
37
Q

HLA-DM

A
  • CLIP is released from MHC-II/CLIP complex by binding of HLA-DM
  • Pathogen peptides derived from endocytosed antigens can now bind to MHC-II
  • The MHC-II/peptide complex travels to cell surface where it is expressed
38
Q

Presentation of cytosolic antigens

A

Cytosolic antigens are presented by nucleated cells to CD8 + cytotoxic T lymphocytes (CTLs) , which kill (lyse) the antigen-expressing cells

39
Q

Presentation of extracellular antigens

A

Extracellular antigens are presented by macrophages or B lymphocytes to CD4 + helper T lymphocytes, which activate the macrophages or B cells and eliminate the extracellular antigens

40
Q

Cross presentation

A

Presentation of exogenous antigens on MHC Class I molecules to initiate CD8+ T cell responses

41
Q

Immunodominant peptides

A
  • Protein antigens are processed to generate multiple peptides
  • Immunodominant peptides are the ones that bind best to
    the available class I and class II MHC molecules
  • Thus elicit strongest T cell response
42
Q

Example of immunodominant peptide in therapeutics

A
  • Peptides produced by mutated genes in cancers are analysed for their ability to bind to the MHC-I molecules in each patient with cancer.
  • The ones that bind are most likely to stimulate antitumor immunity in that patient.