8 - Antigen Presentation to T cells

Question 1

Routes of antigen entry

Answer 1

• 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

Question 2

How are peptides shown to T cells

Answer 2

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

Question 3

Naive T cell activation

Answer 3

Clonal expansion and differentiation into effector T cells

Question 4

Effector T cell activation

Answer 4

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

Question 5

How do T cells recognise peptide antigen

Answer 5

In context of MHC molecules

Question 6

Antigen processing

Answer 6

Conversion of native proteins into MHC associated peptides

Question 7

Antigen presentation

Answer 7

Display of peptide at cell surface by MHC molecules

Question 8

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

Answer 8

The cytosol or the vesicular system

Question 9

Antigen uptake in Class 1 MHC pathway

Answer 9

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

Question 10

Antigen uptake in Class 2 MHC pathway

Answer 10

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

Question 11

Class 1 MHC pathway

Answer 11

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

Question 12

Class 2 MHC pathway

Answer 12

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

Question 13

Dendritic cells antigen capture and presentation

Answer 13

• 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

Question 14

Function of tissue resident resting DC in T cell activation

Answer 14

Antigen capture

Question 15

Function of activated DC in T cell activation

Answer 15

Antigen presentation to T cells

Question 16

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

Answer 16

Very high

Question 17

Expression of Fc receptors, mannose receptors on activated DCs

Answer 17

Low

Question 18

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

Answer 18

Low

Question 19

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

Answer 19

Very high

Question 20

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

Answer 20

Short (~10 hours)

Question 21

Half life of class 2 MHC molecules on activated DCs

Answer 21

Long (>100 hours)

Question 22

Conventional (or classical) DCs (cDCs)

Answer 22

• 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.

Question 23

Two groups of cDCs

Answer 23

• 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)

Question 24

Plasmacytoid DCs (pDC)

Answer 24

• 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.

Question 25

Monocyte derived DCs (moDC)

Answer 25

Can be induced to develop from monocytes under inflammatory conditions

Question 26

Langerhans cells

Answer 26

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

Question 27

Examples of antigen that use MHC class 1 pathways

Answer 27

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

Question 28

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

Answer 28

• 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

Question 29

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

Answer 29

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

Question 30

MHC-1 expression

Answer 30

• 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

Question 31

Defective ribosomal proteins

Answer 31

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

Question 32

Acidified endocytic vesicles in MHC class 2 pathway

Answer 32

• 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

Question 33

MHC-2

Answer 33

• 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)

Question 34

Function of invariant chain li

Answer 34

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

Question 35

Where is li cleaved into CLIP

Answer 35

Acidified endosome

Question 37

HLA-DM

Answer 37

• 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

Question 38

Presentation of cytosolic antigens

Answer 38

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

Question 39

Presentation of extracellular antigens

Answer 39

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

Question 40

Cross presentation

Answer 40

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

Question 41

Immunodominant peptides

Answer 41

• 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

Question 42

Example of immunodominant peptide in therapeutics

Answer 42

• 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.