HLA and antigen processing Flashcards
HLA
Human leukocyte antigens
function as antigen presenting structures to t cells b/c T cells do not recognize antigens in free or soluble forms
Differences in HLA molecules expressed by an individual will influence the repertoire of antigens to which T cells can respond
HLA gene
highly polymorphic (many different alleles are present in the population)
more than 150 separate alleles
Has class II, class III and class I regions
what does class III code for?
cytokines and complement proteins
HLA haplotype
the total set of HLA alleles present on each chromosome
encode protein antigens central for immune system to discriminate self and non-self
most humans heterozygous with two haplotypes (one from mom and dad)
Co-dominant expression
both parental haplotypes expressed simultaneously (so 6 different alleles)
this generates more diversity by increasing the number of different MHC molecules that can present peptides to T cells
very important in transplant b/c want the best match between recipient and donor for both class I and class II genes
MHC class II expressing cell types
Dendritic cells
macrophages
B cells
CD4 T helper cells interact with these cells
MHC class I expressing cell types
All nucleated cells
CD8 CTLs can kill any virus-infected cell
Gene regions encoding Class I HLA
HLA-A
HLA-B
HLA-C
Class I HLA
expressed on all nucleated cells
present antigen to CD8+ cytotoxic T cells
in innate immunity –> functions as the inhibitory receptor for NK cells
RBC’s
don’t have nucleus
RBCs do not express the activating ligand for NKs so not expressing the inhibitory ligand (Class I HLA) is irrelevant.
if you can’t start the process you don’t have to worry about inhibiting it
where is greatest polymorphism in Class I HLA? what is unique about it
in the peptide binding groove b/w alpha 1 and alpha 2
binds peptides about 8-10 aa in length and cannot bind any bigger b/c it has closed ends
each allele of Class I HLA has a different range of peptides that can bind in the groove so when coexpressing all alleles can bind a greater number of peptides
what is unique about the alpha 3 domain of the class I HLA
is not polymorphic, conserved amino acid sequences b/c this is where the TCR coreceptor CD8 binds so it has to be the same for everyone
Beta2 microglobulin portion of the Class I HLA
Non HLA encoded
same for everybody!
associates non-covalently with alpha 3 domain (NOT Covalently)
Class I HLA structure
alpha chain- 3 of 4 globular domains, HLA encoded
beta domain- non HLA coded
Class II HLA
aka D region
genes encoding HLA Class II
HLA-DP
HLA-DQ
HLA-DR
Class II HLA
Primary on antigen presenting cells (macrophages, dendritic cells and B cell)
presenting antigen to CD4+ Tcell
Structure
alpha and beta chains both encoded by HLA-D gene region
alpha and beta genes are strongly associated but NOT covalently linked
peptide binding groove between alpha and beta change is the site of the greatest polymorphism
what is unique about the beta 2 region on the Class II HLA
this is highly conserved b/c this is where CD4 binds
what is unique about the peptide binding groove in class II HLA
formed at the junction of beta 1 and alpha 1
binds peptides between 13 and 18 aa long
OPEN ENDS allow larger peptides to bind
how many class I molecules can be expressed on cells?
Because there are three polymorphic class I genes, called HLA-A, HLA-B, and HLA-C in humans, and each person inherits one set of these genes from each parent, any cell can express six different class I molecules
what is unique about the synthesis of class II HLA
synthesized in the ER and interact with a third protein called the invariant chain
helps keep alpha and beta together
also blocks peptide binding groove until reaches endocytic compartment
in the endocytic compartment invariant is degraded, peptide comes in from endocytosis, binds to class II
where do peptides that present on MHC class II come from ?
outside world
where do peptide that present on MHC class I come from ?
cytosol (inside world)
Class II HLA features of diversity/genetic polymorphism
any alpha chain allele may associate with any beta chain allele, which leads to a greater range of peptides that can bind to class II HLA
Peptide binding of peptide binding groove
looking for size and shape of Peptide
the rest of the peptide that is not bound (the lateral surface or side of the peptide) sticks out of the cleft and this is what is recognized by antigen receptors on T cells
how many peptides can an HLA molecule bind at a time?
one
antigenic peptides and HLA association
slow on rate and very slow off rate
saturatable and low affinity interaction
how many peptides can an HLA bind?
same molecule of HLA can bind multiple epitopes but NOT at the same time
HLA restriction
The ability of T cells to recognize antigens when associated with the organism’s own HLA haplotype, providing a dual recognition system critical to T-cell function.
CD4 –> recognize Ag bound to Class II
CD8–> recognize Ag bound to Class I
Class I HLA synthesis
alpha chain translated into ER as glycoprotein
in the ER alpha chains interact with B2 chains
class I associates with peptides derived from cytosolic (internal) proteins
HLA/peptide complex transported to the cell surface
APC’s
Antigen presenting cells
Convert proteins to peptides for display
Three main types:
Macrophages
Dendritic Cells
B cells
Thymic epithelial cells can also express Class II HLA during T cell maturation
Dendritic cells
most effective at presenting antigen
pinocytose Ag and process it for presentation
home to T cell rich areas in lymph nodes and spleen
produce co-stimulatory molecules
activate naive CD4 and CD8 t cells
Macrophages
Pinocytose or phagocytose
very good at activating memory T cells
B cells
bind soluble Ag via IgM and IgD
ingest by pinocytosis
bind Ag with high affinity b/c highly specific, thus effective when Ag levels are low
not effective at presenting Ag to naive T cells
very effective at presenting to memory T cells
Capture of antigens
Microbes enter body
Phagocytosed or pinocytosed by APC’s
lose adhesive markers and up regulate CCR7
increase expression of HLA (Both I and II) and B7
HLA-DM
acts as a peptide exchanger, facilitating the removal of CLIP and addition of peptides into class II HLA
Ii (invariant)
occupies the peptide binding cleft of HLA class II promotes folding, assembly, trafficking
is degraded to CLIP by lysosomal enzymes
TAP
transports peptides from cytosol to interior of ER
functions in the pathway of Class I MHC antigen processing
Tapasin
B2 microglobulin is bonded to TAP by this tapasin protein
makes sure there is a class I molecule ready to receive a peptide
Outcomes of Antigen presentation
Dendritic cells–> naive T cell activation
-differentiation into Effector T cells
Macrophages–> effector T cell activation
(cell-mediated immunity) activation of macrophages
B cell–> effector T cell activation
B cell activation and antibody production (humoral immunity)
Cross presentation
Dendritic cells ingest virally infected cells and display Ag to CTL (via class I) and Ths (via class II)
what two effector mechanisms are best able to eliminate microbes that are internalized from the extracellular environment?
T helper cells help B lymphocytes produce antibodies
T helper cells help phagocytes to destroy ingested microbes
these are both done with the use of cytokines!!
neither of these mechanisms (which are of the class II/CD4 + pathway) are helpful in elminating viruses and other pathogesn that survive in the cytoplasm
what is the mechanism that is most effective for eliminating cytoplasmic microbes?
Class I–associated peptides are recognized by CD8 + T lymphocytes, which differentiate into CTLs. The CTLs kill the infected cells and eradicate the infection,
all nucleated cells can be infected with some virus so they all must have class I MHC molecules in order to kill that virus/infection
Ankylosing spondoylitis
Inflammation of spine
individuals (88 percent) express HLA B27
possible that HLA-B27 doesn’t present a critical antigenic peptide
Rheumatic fever
generation of antibodies react against streptococci as well as heart tissue
pt’s who have the HLA-DR4 allele
Sjogren’s syndrome
associated with HLA-DR3
Defect in salivation and lacrimination
Insulin dependent diabetes
associated with HLA-DQw8
Psoriasis
Associated with HLA-B3
Processing defects?
leads to cancers
neuroblastoma
renal carcinoma–> class I antigen processing
non-responder
if you do not have the genetics that allow a certain peptide to be bound in the peptide binding groove….the T cells can never respond to the antigen b/c they can never see it and nothing can be done about this
every immune response is poly-clonal why?
because you are seeing different parts of the antigen as it is being processed
so have many different antigen peptides presented for one antigen/infection/virus
