Antigen Recognition by T lymphocytes

describe a t-cell receptor

membrane-bound heterodimer that resembles the Fab region of an antibody

• alpha chain: 40-50 kDa

• beta chain: 35-46 kDa

regions of hypervariability

loops on the variable regions farthest away from the constant regions on each the alpha and beta chains

• called the CDR (complementarity-determining regions) 

the functional t cell receptor complex

the core alpha-beta heterodimer has

• one CD3 gamma

• one CD3 delta

• two CD3 epsilon

• two zeta chains used for signal transduction

strong electrostatic interactions

what is purpose for the other polypeptides associated with the alpha-beta heterodimers

• transport the t cell receptor to the surface

• transduction of intracellular signals when antigen binds

what is the other class of t cell receptors

gamma-delta

• recognize wider variety of antigens

MHC class 1

one polypeptide anchored in the membrane, 3 extracellular domains (alpha chains)

• 4th domain not anchored to membrane (beta2- microglobulin)

• presents antigens of intracellular pathogens

MHC class 2

two polypeptides anchored in the membrane, 2 domains per peptide (2 alpha chains together, 2 beta chains together)

• presents antigens of extracellular pathogens

how does MHC present intracellular pathogen

1. proteins from the intracellular pathogen will be degraded in the cytosol by proteasome

2. at the ER, calnexin is used to bind beta2-microglobulin to MHC class 1 heavy chain

3. calnexin leaves

4. TAP, tapasin, ERp57, calreticulin, and MHC class 1 bind together to form peptide loading complex (bound to each other in that order) *calreticulin bound to glycan on MHC class 1

5. peptides from pathogen travel to the ER through the TAP (transporter associated with antigen processing) protein and bind to MHC class 1

6. they dissociate from the peptide-loading complex and travel to the surface of the cell

• be able to label diagram

how does MHC present extracellular pathogens

1. proteins from the extracellular pathogen will be in early endosome with inactive proteases

2. vesicle acidifies and activates proteases

3. MHC class 2 will be in the ER. it will leave the ER, attached to invariant chain, and travel to the vesicle containing the protein from the pathogen

4. on the way there, the varient chain is cleaved, leaving the CLIP fragment bound to MHC class 2

5. once that vesicle merges with vesicle containg pathogen fragments, DM will release CLIP from MHC class 2, allowing pathogen to bind

6. MHC class 2 will bind to pathogen and bring it to cell surface

which t cell recognize mhc class 1

cytotoxic t cell

• cd8 glycoprotein t cell co-receptor

which t cell recognize mhc class 2

helper t cell

• cd4 glycoprotein t cell co-receptor

structure of cd4

single polypeptide with 4 domains, hinge region in between domains 2 and 3

structure of cd8

heterodimer of two chains, each has one extracellular domain

what happens when cd8 cytotoxic cell recognize mhc class 1 antigen

kill the cell

what happens when cd4 helper t cell recognize mhc class 2 antigen

mhc on macrophage

• cd4 cell will secrete cytokines to help macrophage increase capacity to kill bacteria

mhc on b cell

• cd4 cell secrete cytokines to promote differentiation into plasma cells that will make bacteria-specific antibodies

what does HIV do

binds to CD4 and CCR5 receptor on T cell and enter the cell

• eventually number of CD4 t cell decline

• decline in adaptive immune response to other pathogens, making those pathogens cause of death not HIV

the MHC fold

alpha 1 and alpha 2 domains of mhc class 1 has alpha helical region and beta pleated sheets

which mhc class 1 domain does cd8 bind to

alpha 3

which domain of mhc class 2 does cd4 bind to

beta 2

compartments in the MHC class 1 pathway

cytosol and nucleus

compartments in the MHC class 2 pathway

ER. golgi apparatus, endocytic and exocytic vesicles, lysosomes

once it is in the ER and bound to MHC class 1, what modifications can peptides from pathogen undergo

if peptides too long, ERAP-1 and ERAP-2 will trim the polypeptide to form a nonamer at the amino terminus

purpose of tapasin

1. a low-binding affinity protein will bind to MHC class 1

2. tapasin will bind to alpha 2 to widen binding groove, releasing the protein

3. a high-binding affinity protein will bind to MHC class 1, narrowing the groove, and forcing tapasin to dissociate

which cells have mhc class 1

nucleated cells which are susceptible to viral infection, resting t cells, neutrophils

which cells have mhc class 2

professional antigen presenting cells (macrophages, b cells, dendritic cells)

• these should have mhc class 1 too

invariant chain

blocks proteins from binding to mhc class 2 while in the ER

• MHC class 2 binding pocket will still be blocked when leave ER but by CLIP, a frgment of invariant chain. it is displaced when mhc class 2 merges with vesicle containing pathogen fragments 

how big peptide can mhc class 1 bind

8-9

how big peptide can mhc class 2

10-25

TAP

transporter associated antigen processing