Lec 11: MHCII and DCs Flashcards
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If there are 10^15 different possible T cell receptors, how can 6 invariant molecules (MHCI = HLA-A, HLA-B, HLA-C and MHCII= HLA-DR, HLA-DQ, HLA-DP) have the capacit to present 10^15 peptides
Due to the extreme polymorphism at the species and individual level
Thousands of alleles that are co-dominantly expressed
Each cell can express 10^5 different MHC molecules
MHC binds anchor domains whcih ancohor peptides wiht different comformations
What is teh MHC complex also known as
the HLA (human leukocyte antigen) complex
What are the three major classes of molecules found encoded within the MHC locus
Class 1/2/3 MHC genes
as well as complents and inflammation proteins (MHC 3??)
MHC II structure
member of the ig superfamily
MHC II recombinaiton leads to heterodimeric proteins, with both a and b chains passing though the plasma membrane
a peptide bindng cleft is formed by the pairing//bridging of the a1 and b1 domains
accommodates peptides of 13-18 aa in length (these ones stick out of the cleft)
MHCII molecules exhibit polymorphism in the poptide binding region
MOTIFS and ANCHOR residues
MOTIF : common sequence in a peptide antigen that binds an MHC molecule less evident in MHC II peptides
ANCHOR RESIDUES: some aa anchor the peptide into the groove - not just localized to N and C termini for MHC II binding peptides
Extends other aa residues from groove to interact with TcRs - can be trimmed
peptide groove on both ends allows for 13-18 aa peptides
Promiscuous
a given MHC moleucle can bind numerous different peptides, and some pepties can bind to several different MHC molecules as long as they have a similar motif
what are the predominant MHC II types
DRB1
MHC II allelic variation in humans
again, transmitted in a haplotype.
-> allelic forms of MHC are inherited in linked groups known as haplotypes
one haplotype from the mother, and one from the father, moreover, each individual igg domain can undergo reassortment which increases flexibility with diffrent pairings
codominant expression of alleles
purpose of MHC diversity
provides flexibility in responding to unexpected environmental changes, now and in the future
MHC polymorphisms
pg 258-263
co-dominant expressionof both haplotypes
-> express foth a and b chains
HAPLOTYPES NAD RECOMBINAITON
Why are MHC polymorphisms important
survival of th species (not the individual)
lack of diversity in alleles can lead to population collapse because they are unable to protect themselves agaisnt pathogens
-> if only few MHC alleles are present the pathogen could mutate to gain a fitness advantage and we would die
Pathogen reproductiona nd MHC allele polymorphism
pathogens reproduce faster than humans and their mutation rate is higher.
- > pathogens will always outpace teh counter evasion measures that involve MHC mutations
- > the ultimate number of MHC types are limited
To counteract teh superior adaptability of pathogens humans must possess variants of each type of MHC molecules,
- > moreover, not all MHC moleucles may protect an individual from infection -> may require a specific compliments/ pair
- > a large number of MHC variants ensures that as a whole the population is protected from extinction
HLA DRB1 alleles affect the clinical course of chronic lymphocyte leukemia
see slides
antigens associated with the cancer are better presented on DRB1+
-> survival is haplotype dependent
Contrast the diversity of TCR/ BCR and MHC polymorphisms
Tcr and Bcr change in the individuals of a population (they are in constant fluc)
whereas the type and varient of MHC molecules does not vary in the lifetime of an individual
diveristy of MHC variants is at the population lelve
MHC II antigen processing
figure 7-17 on exam
MHC II presents extracellular antigen peptides
MHC II is primarily restricted to APCs
present peptides to CD4+ T cells
Different capability to present antigens may dicate overall strength of response from individual to individual
HLA-DM
regulates peptide loading og MHC II molecules
their enzymatic fcn is to catalyze peptide cleavage
HLA-DO
acts as a substrate mimic to competitively inhibit HLA-DM-mediated catalysis of MHC II peptide exchange
blocks peptide grove
- > removed leaving CLP after digestion
- > conformational change induces CLP to leave
- > prevents any ol’ peptide from binding
What are the roles of HLA-DM and HLA-DO
???
Which receptors discriminate self and non-self peptides
TCR
Remember, MHC moleucles do not discriminate self and non-self peptides, this discrimination is the function of TCR
Loads Loads what ever is their in there microenvirome.
They then determine what if self or non self peptides have been loaded
Recall, just beacuse it is presented, does not mean that it wil be recognized
T cells only recognize their cognate receptor/ antigen pair
DC’s however will express all sorts on antigen
Stages of DC maturation
differentiation
antigen uptake and innate immune sensing
antigen processing and presentation
phenotype maturation (Cell surface markers)
Functional maturation (Cytokines and co-stimulaiton)
DC phenotype maturation
change in cellular morphology
up-regulation of co-stimulatory molecules
CD86 (constitutive expression)
increase of CD80, a co-stimulatory molecule)
increase of ICOSL, a co-stimulatory molecule
increase of CD83, a marker of a mature DC
DC functional maturation
ability of DC to activate T cells
presence and type of antigen presented
presences and type of co-stimulatory molecules
secretion and type of cytokines
Give an example of a DC-T cell stimulatory activating or inhibiting signal
???
Why does the DC maturation state matter
immature DCs express low levels of CD80/86 and strong ICOSL signals
-> stabalizes IL-10R on the surface of Naive T cells
IL-10 secretionby immature DCs promotes differentiation of anergic T cells or T regs
Mature DCs provide strong CD28 stimulation and promote effector T cell differentiation
see slides, but it basically determines if a T cell will be directed towards immunity or tolerance
Dc migration to lymph node
need to stop picking up antigen before migration => want to present a ‘snap-shot’ of the microenviroment they came from
many DC types reside at the barrier sites such as the skin and mucosa surfaces
DC maturation dramatically enchances theri migratory capacity
- > upregualtion of CCR7
- > Traffic to T cell areas of secondary lymphoid organs
activated DCs cease any further antigen uptake
-> reflect the current state
Distinct DC subsets are found in the blood, secondary lymphoid tissues as periphery
conventrional DC: antigen processing and presentation
langerhans cells: resident DCs in the skin
Plasmacytoid Dc: Major IFN producers in viral infection
Monocyte-derived DC: drive inflammation-> late to the party
conventional DC
antigen processing and presentation
langerhans cells
a type of DC
resident DCs in the skin
Plasmacytoid DC
Major IFN producers in viral infection
Monocyte-derived DC
drive inflamation and late to the party
