Lecture 5 - MHC

Question 1

What’s the main rule regarding transplantation?

Answer 1

Iso/samegrafts succeed allo(different)grafts fail

Question 2

What does MHC stand for and what does it dictate?

Answer 2

MHC = major histocompatibility complex. A set of tightly linked genes which dictate histocompatibility or incompatibility

Question 3

What does azythmic mean and what happens when allografts are given to azythmic recipients?

Answer 3

Azythmic = no T cells. Allografts survive with azythmic recipients indicating rejection of allografts is T cell dependent

Question 4

What’s an example of a minor histocompatibility antigen?

Answer 4

Y chromosome or X chromosome

Question 5

What does MHC encode?

Answer 5

Cell surface proteins which define self

Question 6

How are MHC alleles expressed (genetically)?

Answer 6

Co-dominant fashion

Question 7

How would a hybrid mouse react to allograft from a mouse homozygous for one of its MHC alleles?

Answer 7

Would accept since the hybrid mouse has both alleles

Question 8

Describe the MHC residues which bind the T cell receptor?

Answer 8

Polymorphic so they vary widely from individual to individual in a population

Question 9

What does MHC polymorphism mean for T cell receptr binding?

Answer 9

T cell receptors from one person will bind MHCs from that person but not from others who don’t share the same MHC genes

Question 10

How do peptide antigens associate with the antigen binding pocket of MHC molecules?

Answer 10

Via anchor residues which fit well into the MHC pocket

Question 11

How do peptide antigens provide specificity for the T cell response while bound to MHCs?

Answer 11

Have T cell contact residues which fit into the T cell receptor

Question 12

What is the concept of MHC restriction?

Answer 12

T cells will only respond to other cells that express self-MHC molecules and that also express the specific peptide antigen for which the T cell receptor has reactivity.

Question 13

Describe the T cell receptor?

Answer 13

Composed of two proteins, one alpha and one beta chain which each have a constant and variable region (which dictates specificity)

Question 14

How is the T cell receptor different from B cell antigen receptor/immunoglobin?

Answer 14

It’s not secreted and only binds to antigen found on the surface of other cells (unlike Ig/abodies which can bind to soluble antigens)

Question 15

How does MHC restriction help fight viral and bacterial infections?

Answer 15

Cytotoxic T cells can recognize host cells invaded by viruses and kill them. Helper T cells can recognize host cells that have engulfed bacteria and initiate an inflammatory response.

Question 16

How do T helper cells control infection?

Answer 16

Initiate activation of CTLs, stimulate B cells to secrete more/better abody, activate macrophages and PMNs

Question 17

What are the two classes of MHC and the types of T cells they present to?

Answer 17

MHC class 1 expressed on all nucleated cells presents to CD8+/cytotoxic T lymphocytes, usually from endogenously produced antigens. MHC class 2 expressed only on antigen presenting cells (APCs) which also express MHC class 1 and capture exogenous ag to present to CD4+/helper cells.

Question 18

Which cell types act as APCs?

Answer 18

Macrophages. Dendritic cells (present after ag binding and maturation, best at it). B cells can capture soluble ag to present to T cells. Thymic epithelia

Question 19

Where are DCs located?

Answer 19

Nearly all epithelial surfaces. Called Langerhans in skin. In most sites where antigen may enter.

Question 20

What do DCs do once they bind Ag?

Answer 20

Lose adhesiveness. Migrate via afferent limpatic vessels/chemokynes. Mature (express more T cell activating molecules) during migration due to stimulation by pathogen product/inflammatory signals. Travel to secondary lymphoid organs where they talk to ag specific T cells in T zones

Question 21

What’s the difference between peptides presented by Class 1 and class 2MHCs?

Answer 21

Peptides expressed by class 1 come from endogenously synthesized proteins. Peptides expressed by class 2 come from ingested material.

Question 22

What do other MHC-like molecules do?

Answer 22

Present non-peptide ag e.g. lipids to unique populations of lymphocytes. Have similar strucutres to Class 1 MHCs

Question 23

What’s the structure of MHC class 1 molecules?

Answer 23

Multiple gene loci; in humans HLA (human leukocyte ag) A, B, C. Single polymorphic heavy a chain and non-MHC encoded non polymorphic light chain called B2 microglobulin B2m

Question 24

What is the expression of MHC class 2 molecules induced by and why?

Answer 24

Interferon-gamma (INF-y) or tumor necrosis factor (TNF) which are inflammtory signals. Make APCs better able to present ag

Question 25

What's the structure of MHC class 2 molecules?

Answer 25

Two polymophic MHC encoded chains a and B

Question 26

Why do most individuals express 6 different MHC class 1 and 6 different MCH class 2 molecules?

Answer 26

3 sets each of class 1 genes and class 2 genes from both parents (3x2 for class 1, 3x2 for class 2)

Question 27

Why do offspring tend to inherit the entire maternal or paternal cluster of MHC genes?

Answer 27

Because there is little crossing over within the MHC locus

Question 28

How many HLA haplotypes does everyone have?

Answer 28

2, one from mom one form dad

Question 29

Where do peptides bind to MHCs?

Answer 29

In the antigen binding groove like a hotdog in a bun

Question 30

Why is the codominant expression of MHC alleles significant?

Answer 30

Doubles the number of possible antigens that any individuals MHC molecules can potentially present

Question 31

What is the significance of polymorphic genes for MHCs?

Answer 31

Ensures that different individuals are able to present and respond to different microbial peptides

Question 32

What's the off rate for MHC molecules?

Answer 32

Very slow. Bind peptide long enough to be located by T cell

Question 33

How do class 1 and 2 MHCs capture and present peptides?

Answer 33

Class 1 peptides bind to cytosolic peptides which were transported into the ER/synthesized w/in host cell by TAP. Class 2s bind to peptides in endocytic/endosomal vesicles after DM competes away invariant chain

Question 34

What are the three mechanisms by which APCs take up antigen?

Answer 34

Phagocytosis by macrophages (and also DCs to some extent). Antigen internalization by B cells. Non-specific uptake/pinocytes by DCs

Question 35

Why does TAP deficiency lead to SCID?

Answer 35

TAP usually transports endogenous ag to surface of class 1 MHCs, w/o TAP peptides aren't available for class I to bind

Question 36

How do tumors take advantage of MHC restriction?

Answer 36

Evade T cell responses by downregulating expression of MHC class 1, B2m or TAP

Question 37

How do viruses take advantage of MHC restriction?

Answer 37

Evade T cell responses by downregulating genes, or by interfering with TAP function, MHC class 1 assemble and MHC class 1 transport

Question 38

How do some bacteria take advantage of MHC restriction?

Answer 38

Interfere with endosome to lysosome transport thus keeping their antigens away from class II

Question 39

How can SCID be a class II MHC defect?

Answer 39

One genetic SCID is due to failed expression of MHC class II

Question 40

Why can transfer of T cells from donor to recipient be risky?

Answer 40

Graft vs host disease, attack of host tissue by graft-derived lymphocytes

Question 41

What are two ways T cells can respond to foregin MHC?

Answer 41

The T cell can recognize the allogenic MHC as self but the allogenic MHC has residues which mimic foreign peptide, leading to rejection. Or the allogenic MHC and the bound peptide together both look foreign and trigger response.

Question 42

How does indirect allorecognition work?

Answer 42

Allogenic tissue cells die and are taken up by dendritic cells and are presented as foreign antigens to the T cells

Question 43

So what should transplant doctors look for in a donor?

Answer 43

Donors who share as many HLA alleles as possible (some HLA loci more important than others) but minor histocompatibility regions still an issue