8 - Antigen Presentation to T cells Flashcards
Routes of antigen entry
- 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
How are peptides shown to T cells
By APCs (Dendritic cells, macrophages, and B cells)
Naive T cell activation
Clonal expansion and differentiation into effector T cells
Effector T cell activation
- Activation of macrophages (cell mediated immunity)
- B cell activation and antibody production (humoral immunity)
How do T cells recognise peptide antigen
In context of MHC molecules
Antigen processing
Conversion of native proteins into MHC associated peptides
Antigen presentation
Display of peptide at cell surface by MHC molecules
What are the 2 different intracellular compartments that MHC class 1 and 2 molecules deliver peptides to the cell surface by
The cytosol or the vesicular system
Antigen uptake in Class 1 MHC pathway
Cytosolic protein (endogenous pathway - used for viruses and intraceullar bacteria)
Antigen uptake in Class 2 MHC pathway
Endocytosis of extracellular protein (exogenous pathway - protein comes from outside cell)
Class 1 MHC pathway
Protein antigens in the cytosol are processed by proteasomes, and peptides are transported into the ER, where they bind to class I MHC molecules
Class 2 MHC pathway
Protein antigens that are degraded in lysosomes bind to class II MHC molecules
Dendritic cells antigen capture and presentation
- 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
Function of tissue resident resting DC in T cell activation
Antigen capture
Function of activated DC in T cell activation
Antigen presentation to T cells
Expression of Fc receptors, mannose receptors on tissue resident resting DCs
Very high
Expression of Fc receptors, mannose receptors on activated DCs
Low
Expression of molecules involved in T cell activation (homing): B7, ICAM-1, IL-12 on tissue resident resting DCs
Low
Expression of molecules involved in T cell activation (homing): B7, ICAM-1, IL-12 on activated DCs
Very high
Half life of class 2 MHC molecules on tissue resident resting DCs
Short (~10 hours)
Half life of class 2 MHC molecules on activated DCs
Long (>100 hours)
Conventional (or classical) DCs (cDCs)
- 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.
Two groups of cDCs
- 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)
Plasmacytoid DCs (pDC)
- 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.
Monocyte derived DCs (moDC)
Can be induced to develop from monocytes under inflammatory conditions
Langerhans cells
- Earliest DCs identified
- Function similar to that of cDC2
- Develop early in life
Examples of antigen that use MHC class 1 pathways
Antigens from cytoplasmic cellular proteins, from intracellular pathogens, or from tumour proteins
Transport of peptides from cytosol to ER in MHC class 1 pathway
- 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
What happens to peptides too long to bind to MHC 1 molecules
Can be trimmed with an aminopeptidase, endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP)
MHC-1 expression
- 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
Defective ribosomal proteins
- DRiPs and proteins marled (ubiquitinated) for destruction are transported into ER by TAP
Acidified endocytic vesicles in MHC class 2 pathway
- 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
MHC-2
- 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)
Function of invariant chain li
Binds to newly synthesised MHC-II and blocks binding of peptides and misfolded proteins found in ER and
during transport of MHC-II
Where is li cleaved into CLIP
Acidified endosome
HLA-DM
- 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
Presentation of cytosolic antigens
Cytosolic antigens are presented by nucleated cells to CD8 + cytotoxic T lymphocytes (CTLs) , which kill (lyse) the antigen-expressing cells
Presentation of extracellular antigens
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
Cross presentation
Presentation of exogenous antigens on MHC Class I molecules to initiate CD8+ T cell responses
Immunodominant peptides
- 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
Example of immunodominant peptide in therapeutics
- 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.
