MCM 2-3 T-Cell Receptors & MHC

Question 1

describe the TCR

Answer 1

T-Cell receptor consists of two chains (alpha and beta), linked by a disulfide bond.

both chains are glycoproteins and contain both constant and variable regions

Question 2

difference between TCR and BCR expression

Answer 2

unlike BCRs, TCRs are not soluble. they only exist on cell surface as a transmembrane receptor

Question 3

The t-cell receptor has no ______

Answer 3

effector function

Question 4

compare the diversity and binding affinities of TCR and BCR

Answer 4

TCR have greater total diversity (100,000x) than BCR, but binds antigens less tightly than BCR

Question 5

unlike BCR, in TCR there are no ________

Answer 5

somatic hypermutations

Question 6

describe the TCR complex

Answer 6

TCR is found on the cell surface associated with other proteins, 8 polypeptides called the TCR complex

alpha/beta chains - bind antigen, form the core TCR. they associate with

• one copy each of CD3gamma and CD3delta
• two copies each of CD3epsilon and CD3zeta chain

Question 7

The TCR (alpha beta subunits) itself is responsible for

Answer 7

recognizing antigens, is unable to signal transduce because of very short cytoplasmic tail

interactions with all of the CD3s within the TCR complex allow for signal to be transmitted

Question 8

what purpose do the CD3’s of the TCR complex serve?

Answer 8

1. allow signal transduction

2. transport of newly synthesized TCR to the surface

Question 9

MHC molecules in humans are called

Answer 9

HLA - Human Leukocyte Antigen

Question 10

What do MHC molecules do and what do they consist of?

Answer 10

they present antigen to T-Cell Receptors

they consist of 2 types of chains, either alpha or beta

Question 11

describe MHC1

where is most variability?

what do they do?

what are some important ones?

Answer 11

consists of three alpha subunits (a1,a2 which make the groove, and a3 which is attached to the cell membrane and associates with Beta subunit)

most variability in this class is in groove region where peptide binds (alpha-2 is where most variability exists)

-bind shorter peptides

they present antigen to CD8+ T-cells (during T cell development, CD8+ cells are selected to bind Class 1)

Important class one molecules include HLA-A,-B,-C

Question 12

describe MHC2

where is most variability?

what do they do?

what are some important ones?

Answer 12

consists of two chains (alpha (a1,a2)/beta (b1,b2) with most variability located in the beta chain

-can bind longer peptides

present antigen to CD4+ T-Cells (during T-Cell Development, CD4+ cells are selected to bind Class II)

HLA-D,-Q

Question 13

describe the features of antigens determine how they bind to or are recognized by MHC1 or MHC2

Answer 13

• while there are specific variable regions in come class1/class2, peptides only need to have a specific anchor reside to bind those regions
• anchor/contact residues (binding motif) are conserved for binding of the peptide to the MHC. Once bound, the other amino acids can be presented to a T-Cell

Question 14

MHC1 are found where and do what?

Answer 14

found on all nucleated cells (not RBCs)

present CYTOSOLIC antigens to CD8+ T-cells

Question 15

MHC2 are found where and do what?

Answer 15

found on antigen presenting cells

presents to CD4+ T-cells antigens that are found on..

1. intravescular pathogens (like mycobacteria and other intracellular bacteria)
2. pathogens taken up from extracellular environment through receptor mediated endocytosis or phagocytosis

Question 16

Antigen processing for presentation by MHC1

Answer 16

Viral infection example

1. viral proteins recognzed, poly-ubiquinated which marks for degredation by proteasome.
2. proteins fragmented into peptides 8-10 aa long
3. peptide bind to protein called TAP (transporter of antigen presentation) in the membrane of the ER
4. TAP:Peptide complex moves to lumen of ER
5. peptide is placed on MHC1 binding groove, displacing self-peptide placeholder
6. MHC:peptide moves to cell surface to be recognized by CD8+ T-cell

Question 17

where are MHC Class I molecules expressed?

Answer 17

on all nucleated cells. RBC’s-erythrocytes have no nucleus so would not express MHC1

Question 18

Antigen processing for presentation by MHC2

Answer 18

1. RME/Phagocytosis ingested antigens taken into phagolysosome and fragmented into by protease (slightly longer peptides than MHC1)
2. peptides move to endosomal compartments and placed into binding groove of MHC2 (displacing CLIP “Class 2 associated invariant chain peptide” which binds MHC2 to prevent binding of self-peptide fragments
3. MHC2:peptide carried to cell surface, recognized by CD4+ T-cells

Question 19

Where are MHC2 molecules found?

Answer 19

subset of hematopoietic cells that are professional antigen presenting cells (APCs)

• dendritic cells
• B cells
• Macrophages

Question 20

what is cross presentation?

Answer 20

the process that allows processing of antigen for binding to both MHC1 and MHC2 in antigen presenting cells

antigen presenting cells have both MHC1 and MHC2 as they are both nucleated(MHC1) and antigen presenting (MHC2)

Question 21

What must the TCR recognize in order to bind?

Answer 21

must recognize both the MHC complex and peptide

recognizing one is generally not enough

must be correct MHC and peptide

Question 22

describe the special case of allo-reactivity

Answer 22

when the immune response is activated during transplant rejection, binding of TCR to antigen may not require the simultaneous binding to peptide antigen AND MHC

Question 23

Polymorphism of the classical MHC loci is due to

Answer 23

allelic variation in the number of allotypes - this produces many HLA types

Question 24

what is an allotype?

Answer 24

allotype is the allele of the antibody chains found in the individual.

Question 25

main distinguishing factor between classical and non classical MHC molecules?

Answer 25

polymorphism

Question 26

MHC molecules are highly polymorphic due to

Answer 26

polygeny of MHC and the codominant expression of MHC genes

Question 27

two factors that result in large number of different MHC molecules all expressed on the surface of cells

Answer 27

1. Allellic variation in the number of allotypes, producing many different HLA types, leads to high levels of MHC polymorphism
2. Polygeny - there are several different MHC genes with similar functions

Polymorphism and polygeny

Question 28

what is an MHC haplotype

why is it important to have more MHC haplotype heterozygosity?

Answer 28

the complete set of alleles (varient genes that can occupy a single locus) found within an animals MHC

everyone has a different MHC haplotype

-you will be able to recognize and present more foreign antigens on cell surface - allows you to activate more pathogen-specific T-CElls (explains inbred population susceptibility to certain diseases/infections, they generally have homozygosity)

Question 29

how are MHC alleles inherited and expressed?

benefit?

Answer 29

one from each parent, codominant

codominant expression of both alleles will allow presentation of more peptides from any pathogen than more related haplotypes so are able to activate more pathogen-specific T cells and better protect against infection

Question 30

more polymorphic or divergent haplotypes will allow…

Answer 30

presentation of more peptides from any pathogen than more related haplotypes so are able to activate more pathogen-specific T cells and better protect against infection

Question 31

strong associations between certain HLA types and

Answer 31

autoimmune diseases, some are also protective for certain diseasess

Question 32

Gamma/Delta TCR

expressed where?

diversity level?

what do they do?

Answer 32

expresed on surface of CD4-/CD8- cells

less diverse than alpha/beta

function unclear

Question 33

what do superantigens do?

Answer 33

function as bridge between certain TCR variable genes and MHC

no antigen processing/presentation necessary by MHC for binding to TCR

Question 34

Frequency of superantigen specific T-cells vs conventrional antigen T-cells?

superantigens include…

Answer 34

T-cells specific for superantigens occur at higher freuqnecy than for conventional antigens

bacterial enterotoxins, staph, strep, mycobacterial

Question 35

effect on presenting cell
MHC1
MCH2

Answer 35

MHC1 - presenting cell is killed

MHC2
i. If Intravesicular pathogens: presenting cell (Macrophage) is activated to kill intravesicular bacteria (mycobacteria and other intracellular parasites) and parasites

If extracellular pathogens and toxins: presenting cell (B-Cell) is activated to secrete Ig to eliminate extracellular bacteria/toxins

Question 36

gamma:delta is…(4)

Answer 36

recognition of antigen is not restricted by MHC
expressed on CD4-CD8- t-cells
function unclear - possible tissue homeostasis

Question 37

superantigens

Answer 37

-function as bridge between certain TCR-V genes and MHC

• include bacteria exotoxins - staph, strep, myco
• no antigen processing or presentation by MHC required for binding to TCR
• t cells specific for superantigens occur at higher frequency
• activation of many t-cells = cytokine storm

Question 38

how does a helper T cell interact wiht macrophage?

Answer 38

CD4

Question 39

Relative Risk (RR)

Answer 39

MHC+/- in individuals WITH disease vs WIHOUT disease

RR1 of 1 = allele is expressed with same frequency in the patient and population, confers no increased risk

RR greater than 1 = indicates association of allele with disease