Antigen Presenting Molecules and Cells

Question 1

Which cells express MHC-I and MHC-II molecules?

Answer 1

-MHC-I are expressed by all nucleated cells

-MHC-II molecules are expressed in antigen-presenting cells such as macrophages, B-cells, and dendritic cells

Question 2

What is another term for MHC for humans?

Answer 2

HLA

Question 3

Describe the structure of the MHC-I molecule:

Answer 3

-Heterodimeric, the binding pocket consists of 1x α chain
-binding of 8-10 amino acids (PAMPs) on the pocket with α1 and α2 chain
-the smaller ß chain stabilizes the larger α chain
-α3 transmembrane region

Question 4

Describe the structure of the MHC-II molecule:

Answer 4

-Heterodimeric, with both α1 chain and ß1 chain binding 13-18 amino acids
- α2 chain and ß2 chain pass through the membrane

Question 5

Interaction of binding protein with pocket region:

Answer 5

For MHC-I binding to peptides a bulge is formed by the peptide, bc some AA are not binding between -> creating a gap -> bulge

For MHC-II all AA are binding without a gap -> no bulge

Question 6

Why do different MHC bind different epitopes?

Answer 6

-Because different MHC proteins bind different anchor residues on antigenes

-Anchor residues can change due to MHC mutations

Question 7

Why is it important to have different MHC proteins?

Answer 7

Because particular MHC proteins bind to particular regions (residues) on a PAMP, to present as much as possible we need more MHC proteins covering many residues on a PAMP

Question 8

Why are MHC proteins inheritable?

Answer 8

Because they are located in one cluster on Chromosome 6
e.g. T and B-cells genes are spread on multiple chromosomes

Question 9

How can MHC molecules increase immunity to different pathogens?

Answer 9

Through polymorphism in the binding region, several hundred allelic variants
-one MHC molecule can bind different peptides, and some peptides can bind to different MHC molecules

Question 10

How many MHC molecules are encoded in humans?

Answer 10

MHC locus encodes 3 major classes: MHC-I, II, and III
-3 versions of class I α subunit * 2(maternal or parental) = 6x class I
-3 versions of class II α subunits + 3 ß subunits *2 = 12x class II
-MHC III is for proteins of the complement and inflammation proteins, non-antigen presenting

Question 11

What are other related genes found in the MHC locus?

Answer 11

-Tap proteins: transporter for MHC-I proteins and proteasome components

-HLA-E; G; F for presenting non-classical MHC-I molecules playing a role in innate and adaptive immunity

-(CD1 presents lipids; normal MHC presents peptides)

Question 12

How are MHC genes inherited?

Answer 12

Allelic forms of MHC genes are inherited in linked groups (haplotypes)

-one haplotype from each parent is inherited
-rare cases of recombination within the MHC locus

-in animals, both maternal and paternal versions of a MHC can are expressed

Question 13

Mating of inbred mouse

Answer 13

-A b/b mouse can donate to a b/b because the T-cells of the recipient are b/b so they will accept and recognize b as self —-> but it will not accept k/k bc it is seen as foreign

Question 14

Why is coding for multiple MHC important?

Answer 14

-mutations f.e. if viruses mutate that MHC can’t detect the virus peptide anymore or

cancer: after mutating the proteins may not be self anymore so if you have multiple MHC, the chances are higher to be detected by T-cell

Question 15

MHC-I and MHC-II interact whit which type of PAMPs (cytoplasmic, extracellular)?

Answer 15

-MHC-I interacts with peptides derived from intracellular (cytoplasmic) proteins –> presenting them to CD8+ cytotoxic cells

-MHC-II interacts with extracellular processed antigens –> presenting it to CD4+ helper T-cells

Question 16

Explain the process of MHC-I presentation after cell entry of the protein:

Answer 16

The small peptide pieces are tagged with ubiquitin and fed into Constitutive and Immunoproteasomes

Immunoproteasomes cleave ubiquitinated proteins into fragments that pair better with MHC molecules

Question 17

What happens with the peptides after being ubiquitinated and cleaved?

Answer 17

-MHC-I pairs with ß2-microglobulin
-peptides are processed in the proteasome (in the cytosol) and fed to TAP, a transporter, into the RER -> and inserted into MHC-I -> MHC-I bound to a peptide is exported to the cellular membrane

(happens with host and pathogen peptides)

Question 18

Explain the process of MHC-II presentation:

Answer 18

-in the ER: MHC-II is bound to the invariant chain to prevent premature peptide loading -> transport to Golgi to form an endosome

-extracellular: peptides (host or pathogenic) bind to BCR and are endocytosed; BCR is recycled and the peptide is processed in the endosome

-the fusion of MHC-II and peptide endosome -> the invariant chain that blocked MHC-II is degraded and the peptide is attached to MHC-II -> transit to cellular membrane

Question 19

How can different conditions change MHC expression?

Answer 19

-upregulation in times of infection -> cytoplasmatic PRR helping transcription factors

-cytokines IFN-α and TNF-α drive up MHC expression,
immune suppressors (steroids, anti-inflammatory cytokines) down-regulate the expression

-Viruses like to shut down MHC Class I expression

Question 20

Which molecules present nonprotein antigens and by whom are they recognized?

Answer 20

-CD1 (related to MHC-I) presents lipids, lipid-linked molecules
and MR1 present metabolites for Vitamin B2

-they present pathogen and self lipids (tolerance for self-lipids)

-recognized by T-cells

Question 21

Which cells are the primary Antigen-presenting cells

Answer 21

Phagocytic cells like monocytes, dendritic cells, macrophages, and
neutrophils + B-cells when Ag binds to their BCR

Question 22

Explain the process of dendritic antigen presentation:

Answer 22

-Dendritic cells (+Langerhans cells in the skin) and macrophages are present in the skin, GI system, and mucus membrane and take up self and pathogenic extracellular antigens and express them on MHC-II

-Upon PRR stimulation through PAMPs they increase their migration to secondary lymph organs (lymph nodes, spleen, MALT/GALT) -> presentation to naive T-helper cells

Question 23

How are antigens transported into the secondary lymph organ tissues?

Answer 23

-Small antigens can pass the subcapsular sinus directly, but large ones are captured by subcapsular sinus macrophages (SCSMs) and handed over to B-cells

-Follicular dendritic cells concentrate antigens for selection and differentiation

Question 24

What is the role of Follicular dendritic cells (FDC) in B-cell development?

Answer 24

-They are located in the germinal center of lymphoid organs and bind extracellular Ag and hold them for BCR binding
-> B cell Ag are 3D peptides, not degraded proteins (but can be conformational and linear)

Question 25

What is the role of dendritic cells in T-cell development?

Answer 25

-Interdigitating dendritic cells (IDC) phagocytose and display antigen to T-cells in t-cell rich zones for their activation

-Macrophages and DC migrate to the thymus and help in the development of T helper and cytotoxic T-cells

Question 26

What is the Cross-presentation of antigens by dendritic cells?

Answer 26

-It is to avoid redirection of self-antigens into the antigenpresenting pathway (MHC-II)

-DC presents extragenic peptide by MHC-II to CD4 T helper cell -> T helper identifies non-self and licenses the DC to present the peptide on MHC-I (different pathway and smaller piece) to present to CD8 cytotoxic T-cell