ICL 4.0: MHC and T-Cell Receptor

Question 1

what is innate immunity?

Answer 1

non-specific, first line of defense

cell mediated, some general small molecules

responsible for stimulating adaptive immunity

Question 2

what is adaptive immunity?

Answer 2

very specific, creates long term memory for a pathogen

humoral & cellular mediated

some antigen specific cells stay around after infection to mount faster response upon second exposure

Question 3

what is the most potent APC in the body?

Answer 3

B cells produce antibodies

it’s the most potent APC in the body!

Question 4

what happens when a pathogen enters the body?

Answer 4

tissue macrophages and dendritic cells recognize pathogen and engulf it

dendritic cells then travel to draining lymph node; while they’re traveling they degrade the pathogen

when they get to the lymph node, they settle in the T-cell areas

some pathogen will enter lymph and travel to lymph node on their own

Question 5

what does MHC stand for?

Answer 5

major histocompatibility complex

Question 6

what are the two pathways used to present antigens derived by different pathogens?

Answer 6

MHC I

MHCII

MHCI has 1 transmembrane domain, MHCII has 2 transmembrane domains

Question 7

whats the structure of MHCI?

Answer 7

1 transmembrane domain

α1, α2, α3 domains all associated with β2 micro globulin domain

peptide-binding groove

Question 8

whats the structure of MHCII?

Answer 8

2 transmembrane domains

α1, α2 associated with β1 and β2 domains

peptide-binding groove

Question 9

what happens if there’s β2 deficiency?

Answer 9

you won’t get proper MHCI formation

Question 10

why is antigen presentation and MHC important in medicine?

Answer 10

1. immune response = knowing what’s self and what’s foreign
2. transplant rejection
3. autoimmune disease

Question 11

where is MHCI found?

Answer 11

found on almost every cell type

***except RBC, sperm and brain

Question 12

where is MHCII found?

Answer 12

found only on antigen presenting cells

ex. macrophages, dendritic cells, B cells

Question 13

what’s another name for MHC?

Answer 13

Human Leukocyte Antigen (HLA)

Question 14

which chromosome are MHC genes found?

Answer 14

chromosome 6

Question 15

how many types of MHCI are there?

Answer 15

heterozygotic humans can express 6 different MHC I

HLA-A,B,C are on the surface of the cell and present antigen to cytotoxic CD8 T-cells

HLA-E, G are ligands for NK cells

HLA-F is intracellular (function is unknown)

Question 16

how many types of MHCII are there?

Answer 16

heterozygotic humans can express 8 different MHC II

HLA-DP,DQ,DR present antigen to helper (CD4) T cells

DM,DO regulate peptide loading

Question 17

what are the MHCI isotopes?

Answer 17

HLA-A

HLA-B

HLA-C

HLA-E

HLA-F

HLA-G

Question 18

what are the MHCII isotopes?

Answer 18

HLA-DM

HLA-DO

HLA-DP

HLA-DQ

HLA-DR

Question 19

why do organs get rejected?

Answer 19

because MHCI will be able to recognize that it’s foreign

only 1 in 120 million people match all 3 MHCI alleles…

Question 20

what does MHCI do?

Answer 20

used for presentation of cytosolic antigens (peptides generated within the cell)

generally associated with viral infection but some cytosolic bacterial antigens can be presented on MHC I

Question 21

how does MHCI work?

Answer 21

you get an intracellular antigen that goes through the proteasome where it gets chopped up

then it gets transported from the cytosol to the ER via TAP where it binds to MHCI

MHCI then gets transported to the surface

what’s presented on MHCI are not always pathogenic peptides; your body is always making and degrading proteins and they go through this same pathway!

so hopefully when you’re healthy, you’re just presenting your own peptides that need to be broken down without a T cell response

when you get infected with a virus, it makes viral proteins that will need to get degraded via MHCI and your T cells will sense this and mount a T cell response that wouldn’t otherwise happen if it was self-peptides

Question 22

what are the steps to MHCI presentation?

Answer 22

1. MHCI heavy chain is stabilized by calnexin until β2-microglobulin binds
2. calnexin is released and the heterodimer of class I heavy chain and β2m forms the peptide-loading complex with calreticulin, tapas in, TAP, ERp57 and PDI
3. proteasome breaks down proteins from antigens into peptide fragments
4. a peptide is delivered by TAP binds to the class I heavy chain, forming the mature MHC class I molecule
5. MHCI dissociates from the peptide-loading complex and is exported from the ER to the cell surface

Question 23

why is the peptide binding groove of MHCI important?

Answer 23

the peptide that binds to MHCI only comes into contact with MHCI at specific points

turns out, the points of contact are where all the genetic deficiencies across the population take place

there’s like 500 HLA-A MHCI and depending on which one it is, they might be able to bind a certain peptide better than other people

this is why some people get sick more than others!

Question 24

what are MHCII?

Answer 24

used for presentation of extracellular derived antigens

post-phagocytic/edocytic processing

Question 25

how does MHCII work?

Answer 25

extracellular antigen enters into the cytoplasm antigen is broken down into peptide fragments inside phagolysosome peptides bind to MHCII MHCII is transported to the cell surface

Question 26

what are the steps in MHCII presentation?

Answer 26

1. invariant chain blocks binding of peptides to MHCII molecules in the ER 2. in vesicles invariant chain is cleaved, leaving the CLIP fragment bound 3. CLIP blocks binding of peptides to MHCII in vesicles 4. HLA-DM facilitates release of CLIP, allowing peptides to bind the invariant chain is inhibiting anything from binding; it has to be a very specific thing that actually binds -- this is good because you don't want APC to be activating T cells all the time so CLIP and invariant chain prevent constant peptide binding until the pH decreases; this makes sure you aren't binding your own peptides to MHCII