Antigen Presentation & Processing - Diebel Flashcards
What is anergy?
The TCR recognizes a MHC and binds
but there is NO CD80/86 being expressed on the APC
-T cell will get destroyed/deleted
What does CTLA-4 do on the T cell surface?
~24 hours after T cell activation it will express CTLA-4
CTLA-4 competes with CD28 for binding to CD80/86
It has a higher affinity for CD80/86
Blocks stimulatory effect you get from CD80/86 and is important to prevent overstiumlation
Dendritic cells
What do they do?
How do they express their receptors and costimulatory molecules
- Most effective APC
- Present peptides, viral antigens, and allergens
- Immature in peripheral tissues = low expression of MHC II (so always expressing it)
- Mature in lymphoid tissues = high expression of MHC II
- Constitutively express B7 (CD80/86) and other co-stimulatory molecules
How do DCs take up antigen?
What T cells do they activate?
-uptake antigen by endocytosis and phagocytosis
-activate naive T cells, effector T cells, memory T cells.
When do macrophages express MHC II and their co-stimulatory molecules?
What do they present to T cells?
- They must be activated by phagocytosis and cytokines to express these
- Present particulate antigens to T cells
When do B cells express MHC II and co-stimulatory molecules?
What do they present to T cells?
-Constitutively express MHC II (increases w/ activation)
-must be activated by antigen binding to antibody to express co stimulatory molecules
-Present soluble antigens, toxins, and viruses
Cyctosolic Pathway?
What MHC molecule goes with this?
- Endogenous pathway
- Antigen is inside of cell and gets broken down by proteasome
- Antigen peptides secreted into RER
- Bind to class MHC I molecules
- MHC II loaded with peptide goes to golgi to get brought to the surface for presentation
Endocytic Pathway:
- MHC II is in RER and binding site is occluded
- exogenous antigen is uptaken by endocytosis
- As MHC is travelling from golgi to surface, it fuses with vesicle with antigen peptides
- Presents antigen peptides on surface of cell
Cytosolic Proteolytic System:
- During normal growth cycle you have constitutive proteosome
- Inflammation –> Type 1 IFN produced –> switching of beta subunits (immunoproteasome) –> activity changes –>proteins are cut into different lengths to fit into MHC I molecule groove.
What is the function of TAP1/TAP2?
What size peptide does it like?
- Transporter associated with antigen processing
- Peptide bind to transporter protein heterodimer complex –> TAP1 and TAP2
- Tap1/Tap2 extends across membrane of RER and transports peptides into lumen of the RER
- Tap has affinity for peptides 8-16 amino acids long
Function of ERAAP?
- MHC I is picky and likes peptides to be 9 amino acids long
- ERAAP trims the peptide to this length
What kind of peptides does MHC I like to present?
-its on all cells except RBCs remeber.
-
Defective ribosomal products (DRiPs) - sometimes we just don’t make proteins correctly so we have to fess up, display these mistakes, and get killed
- defective proteins = defective DNA
-
Viral proteins- Virus infected cells have 20S proteasome (induced by IFN gamma and TNF alpha)
- degrades and presents viral proteins
- T cells recognize these proteins and kill infected cells
What chromosome are the instructions for MHC I molecule on?
Most everything is on chromosome 6 (Tap, HLA-A, B, C,
HLA-DQ, DP, DR)
Beta2 microblogulin is on chromosome 15
What is the normal ratio of CD4:CD8 T cells?
2:1
~65% CD4
~35%CD8
How is low MHC I related to low overall T cell #’s, specifically less CD8+ T cells?
In thymus, T cells start as double positive for CD4 and CD8
If you only display 1% of normal MHC I molecules you will mostly select for CD4 b/c most cells will come into contact with MHC II molecules
—-> Less CD8 cells
Function of calnexin?
During MHC I maturation:
MHC I alpha chains will bind to calnexin until Beta2 microglobulin binds, then complex will be released from calnexin
Function of the invariant chain?
Bind to peptide-presentign site and keeps MHC II right conformation to accept a peptide
- Assist in folding of alpha and beta chains
- assists in the transport of MHC II molecule from Golgi to cytoplasmic vesicles
Function of CLIP?
- Proteolytic cleavage digests invariant chain and the short fragment left is called CLIP
- still bound to antigen presenting side of MHC II
Function of HLA-DM
A nonclassical MHC II (never makes it to cell surface) that catalyzes the exhange of antigenic peptide for the CLIP
-HLA-DO regulates the HLA-DM
Cross Presentation of Exogenous Antigen
- DC binds to Th cell and Th cell licenses DC to do cross presentation
- CD40L on T cell does licensing
- DC will go display antigen on MHC I so CD8+ cells can recognize it.
- Ramps up CD+ T cell activation
- While DC is interacting with both Th cell and CD8+, Th will release IL-2 to give proliferation signal to itself and the CD8+ cell :)
MHC II Deficiency:
- Inherited autosomal recessive trait
- You will see earlier infections and more severe (mild form of SCID)
- Watch out for pyogenic and opportunistic infections like Pneumocystis jirovecii
- T cells won’t response to specific exogenous antigenic stimulus- low CD4+ cells
- Immunoglobulins will be really low because Th2 cells can’t help stimulate production of IgG
- Tx: hematopoietic stem cell transplantation
How are infants with MHC II deficiency different from those with SCID?
They still have T cells which can response to nonspecific T cell mitogens such as PHA
In classic SCID you won’t respond to mitogens
What is the lack of MHC II molecules from?
defects in transcription factors required to regulate their coordinated expression
- don’t respond to IFN gamma signal to upregulate MHC II
- Nothing is wrong with the MHC II gene
MHC I deficiency leaves you susceptible to what?
-Increased damge to airways caused by viral infections cuases bronchiectasis
leaves you more susceptible to bacterial infections
*Does NOT directly devrease ability to fight off capsulated bacterial infections
