Immunology Unit 2 - pMHC & MHC complexes

What is the job of MHC Class I molecules?

Present peptide antigens to CD8 T cells

MHC class I is a complex of what two proteins?

glycoprotein ⍺ chain

β2-microglobulin protein

Describe the ⍺ chain of MHC I

Passes through the plasma membrane

Three external domains

Help form the peptide binding groove

What are the three external domains of the ⍺ chain of MHC I

a1, a2, a3

What forms the walls and floor of the peptide binding grrove on MHC I?

a1 and a2 domain bind 8-10 amino acid peptide fragment from an antigen

⍺-helices = walls

β-pleated sheets = floors 

Where is β2m found? What is it?

found on all nucleated cells. Small, soluble proteins 

What peptides are present in the Class I MHC-peptide complex?

• peptides derived from endogenous intracellular proteins 

• Peptides from exogenous proteins by dendritic cells via cross presentation

• Present peptides to TCR on CD8+ cells

CD8 will bind to what part of the MHC I complex? What does this do?

binds to a3 to stabilize pMHC and TCR on the CD8 T cell interaction

What are Anchor residues in MHC I? 

specific types of amino acids at the ends of the peptide that bind tightly in the cleft of MHC and lock peptides into grooves.

What is the job of MHC class II molecules?

Present antigen peptides to CD4+ T cells 

What is the MHC II heterodimer composed of?

⍺ chain

β chain 

In MHC II, the ⍺ and β chains both _________

pass through the plasma membrane

How is the peptide binding cleft formed in MHC II?

pairing of a1 and b1 domains, open on ends (longer peptides 13-18)

two a helices form walls

b sheet forms floor

What are MHC II molecules found on?

Antigen presenting cells: DC macrophages, B cells

MHC I and II are members of what family 

Ig superfamily

What peptides are present in the Class II MHC-peptide complex?

• peptides derived from exogenous extracellular APC processed proteins

• Present peptides to TCR on CD4+ T cells

CD4 binds to what on MHC class II? What does this do?

binds to β2 to stabilize pMHCII and TCR on the CD4 T cell interaction

Where are Anchor residues found in MHC II?

reside in the center of the peptide

Allelic forms of MHC genes are inherited in ________ called ______

linked groupes ; haplotypes 

How do haplotypes inherit?

One haplotype from each parent 

MHC are ________ expressed. Explain

Co-dominantly

Both maternal and Paternal MHC genes are expressed in offspring cells 

Where are polymorphisms found in MHC? How many individual polymorphisms can someone have?

Found in the peptide binding region

Individuals can have 6 unique class I and 12 class II molecules 

What is the benefit of an organism being able to present all possible antigen peptides?

More peptides that can bind, the greater amount of antigens that can be identified 

What makes transplantation difficult?

HLA variation because nonmatching MHC patterns will result in rejection on transplanted tissue 

What percent chance do you have of inheriting the same HLA markers as your sibling?

25%

The classical MHC I genes…

encode proteins expressed on the surface of nearly all nucleated cells 

The classical MHC II genes…

Encode proteins predominantly expressed on antigen presenting cells

MHC class III genes…

encode a diverse set of proteins that have immune function but do not present antigen to T cells

Which class of MHC has an important role in T cell and NK cell function?

MHC I

Viruses shut down MHCI allowing the escape from CD8 T cell killing, this leads to NK killing

MHC ___ expression is cell and tissue dependent, which are expressed on _____, ______, and ______

MHC II

APC (DC, macrophages, B cells)

thymic epithelial cells

activated t cells

MHCI presentation requires _______ or______ processing 

cytosolic, endogenous 

MHCII presentation requires _____ processing 

exogenous (DCs, B cells, macrophages). Must bring into cell 

What is an Endogenous antigen

generated within all nucleated cells from intracellular antigens bc of normal cell metabolism which is presented in class I pMHC to TCRs on CD8 T cells

Endogenous antigens includes peptides from self-proteins. What does this provide?

a way for checking that cells are self and are generally healthy

Endogenous antigens includes peptides from nonself-proteins. What does this show?

shows the cells have been infected with pathogens or are abnormal

Endogenous antigens display what?

non self peptides on class I pMHCI that activate CD8 T cells 

Peptides in the endogenous pathway are generated by what?

protease complexes called proteasome. 

What are used to tag intracellular proteins for constitutive proteasome

ubiquitin

what us a subtle variant that cleaves ubiquitinated proteins into fragments that pair better with MHC molecules?

immunoproteasome 

What is TAP and what does it do?

Transporter associated with antigen processing molecules (in RER)

they move the fragments

What aid in peptide/MHC class I assembly?

chaperones

What help fold MHC class I and put it near TAP?

Calnexin, ERp57, calreticulin, tapasin

What trims long peptides at their amino termini to a suitable size of MHC?

ER aminopeptidase ERAP1

What are exogenous antigens?

taken up from APC from extracellular antigens through endocytosis or phagocytosos and processed into fragments which are presented to pMHC II to TCRs on CD4 cells 

peptides in the exogenous pathway are generated from what?

internalized antigens in endocytic vesicles 

What 2 structures become MHC late lysosome 

Endosomes/phagosomes fused with lysosomes 

What does the invariant chain )li, CD74) do?

transports class II MHC molecules to endocytic vesicles 

class II associated invariant chain peptide is acted on by HLA-DM and HLA-DO. What do these do?

DM - exchanges CLIP for a peptide fragment 

DO- modulates the function of HLA-DM

What cells can cross present exogenous antigens 

DC

What are the only APC to exhibit cross presentation?

DC

What is cross presentation?

when exogenous antigens are redirected to the endogenous  presentation pathway 

What non protein antigen may be recognized by T cells 

C1

Where does presentation of nonpeptide antigens occur?

nonclassical MHC molecules (can present lipids and lipid linked molecules)