MHC -Thrush

Question 1

What are human leukocyte antigens (HLA)?

Answer 1

The same thing as MHC in humans

Question 2

What are the characteristics of class I MHC?

Answer 2

expressed on most nucleated cells
present Ag to CD8+ T cells (ex. Tc, CTL)
HLA-A, HLA-B, and HLA-C in humans

the class I MHC gene encodes for a single chain which when associated with the invariant beta2-microglobulin (NOT on MHC gene) forms the Class I MHC

Question 3

What are the characteristics of class II MHC?

Answer 3

expressed primarily by professional APCs (Macrophages, B cell, DC)
present Ag to CD4+ T cells (ex. Th)
HLA-DP, HLA-DQ, and HLA-DR in humans

are heterodimers coded for by the alpha and beta genes within the MHC locus

Question 4

What are the characteristics of class III MHC?

Answer 4

secreted proteins found in serum
complement proteins, some cytokines (TNF), proteins involved in Ag processing (TAP, LMP2 and LMP7), etc

Not as important in transplant reactions

Question 5

What 2 features of MHC proteins make them highly polymorphic?

Answer 5

1. co-dominance–> both alleles (maternal and paternal) are expressed for each MHC
2. MHC genes are polygenic: there are 3 different MHC class I proteins (ex: HLA-A, HLA-B, HLA-C)–> can get 6 different Class I MHC and 12 different class II MHC proteins

Question 6

Why is it difficult to find a match for organ transplant?

Answer 6

Because MHC genes are polymorphic–> there is a lot of variation in out gene sequence and our bodies are able to tell self vs. non-self via the MHC molecules

significant differences in MHC will lead to the immune system attempting to destroy the foreign tissue.

Question 7

What is a haplotype?

Answer 7

The full complement of genes that an individual has (ex: Alleles for HLA-A, B, C, DR, DQ, DP coming from the maternal side would be considered one haplotype)

Question 8

What is the structure of class I MHC proteins? What T cell binds to them and what domain makes up the binding cleft?

Answer 8

a heterodimer of three alpha chains (alpha1, alpha2, and alpha3) associated with an invariant beta2-microglobulin

-beta2-microglobulin is structurally similar to alpha3

• alpha1 and alpha2 form the peptide binding cleft
• ->holds 8-10 a.a. peptide (pita model) –> anchor residues are a the ends
• -> where most polymorphisms are located

-alpha3 is highly conserved and interacts with CD8

Question 9

What is the structure of Class II MHC proteins? What T cell binds to them and what domain makes up the binding cleft?

Answer 9

Heterodimer of alpha and beta chains
–>encoded for by different genes

protein divided into: alpha1/alpha2 and beta1/beta2

alpha1/beta1 is the Ag binding cleft

CD4 contacts alpha2/beta2 area

accommodates 18-20 amino acids: hot dog model
–> anchor residues can be anywhere in the peptide

Question 10

How is MHC different from antibodies?

Answer 10

MHC can bind to a variety of different antigenic peptides, where antibodies can only bind to one antigen

Question 11

Which class of MHC displays endogenous peptides? What cell recognizes them? What is the preferred length of endogenous peptide?

Answer 11

class I MHC --> to be recognized by CD8+ T cells
(ex: viral antigens that come from within the cell) 

Nonamers are the preferred length of peptide

Question 12

Which class of MHC displays exogenous peptides? What cell recognizes them?

Answer 12

Class II MHC –> recognized by CD4+ T cells

Question 13

What class MHC proteins are found on the “professional” antigen presenting cells?

Answer 13

MHC class II proteins are presented on dendritic cells, macrophages, and B cells.

Question 14

Which cells don’t normally express class II MHCs but can be induced to express them?

Answer 14

human T cells

Question 15

What will individuals with defects in expression of the class II transactivator (CIITA) exhibit? What is this syndrome called?

Answer 15

Defects in CIITA would not allow for the expression of class II MHC protein. 
Without these molecules, T helper cells would not be activated--> the individual would have defects in immune system activity

This is called “bare lymphocyte syndrome”.

Question 16

How are endogenous antigens processed and paired with an MHC? What will recognize this mature Ag-MHC complex?

Answer 16

• Endogenous Ags are tagged with ubiquitin for degradation by the proteosome
• LMP2 and LMP7 are the enzymes that associate with the proteosome to cut protein near the hydrophobic residues (class I anchors)
• degraded proteins are transported by TAP (transporter associated with Ag Processing) to the rough ER where it joins a class I MHC peptide before traveling to the golgi and the cell surface to become a membrane bound protein

will be recognized by the TCR of CD8+ T cells

Question 17

How are these exogenous peptides degraded?

Answer 17

exogenous peptides are degraded by the endocytic pathway (brought into macrophages or DCs via endocytosis and then degraded by the lysosome before joining MHC class I molecules)

Question 18

How are exogenous peptides brought into the cell and processed to be paired with and MHC?

Answer 18

• Macrophages, DCs or B cells bring in exogenous Ags into an endocytic vesicle (phagosome)
• after fusion of endosome with lysosome (low pH), the protein will be degraded
• ->yields peptides of ~13-20a.a. long

-Newly made MHC class II are produced in the rough ER. Invariant chain (Ii) associates with newly made class II (preventing it from binding to peptides)
-As the MHC II travels to the surface, the Ii is partially degraded to yield CLIP
(class II associated invariant polypeptide)
-once CLIP and MHC class II reach the phagolysosome, then the CLIP is removed and the antigenic peptide can associate with MHC class II
-HLA-DM – binds to class II and releases CLIP when Ag peptide is binding

Question 19

What do gamma delta TCRs use instead of MHC and why? What other cells can use a similar system?

Answer 19

-they can recognize non-protein antigens
-Use CD1 molecules instead of MHC
associates with beta2-microglobulin
-CD1 genes on chromosome #1 (not within MHC locus)
-expressed on professional and non-professional APCs, B cells, thymocytes, epithelial cells
-5 different types of CD1
-expression depends on the type/class of CD1
-lipids from M. tuberculosis and M. leprae found to be presented with CD1

-NK cells may also recognize Ag with CD1 (even though they are not antigen specific)

Question 20

Why would we use B cells as antigen presenting cells when DCs and macrophages are great APCs?

Answer 20

Because in low antigen concentrations, the antigen might not be presented enough on the DC and macrophage surfaces to illicit a T cell response

B cells can increase the concentration of antigens to cause an immune response