Lecture 12 Flashcards
what is the MHC complex locus called in mice? what chromosome?
H2
chr 17
what is the MHC complex locus called in human? what chromosome?
HLA
chr 6
how big the MHC locus?
7 million bp
what are 2 genes involved in MHC that are not on the same chromosome as MHC?
B2m and Ii
how are the diff MHC classes organized in the locus?
in clusters
describe beta chain in HLA-DR
2 beta chains in HLA-DR
what is unique about HLA-DM and DO?
non-classical class II molecules
since many genes involved in antigen processing are found on the human MHC locus, what is the significance?
the genes were co-selected during evolution
what is an example of non-MHC genes that are found in the human MHC locus?
complement protein genes
what is encoded in Class I besides HLA-A/B/C?
non-classical classIb genes –> HLA-E/F/G
what is a common inducer of MHC locus genes?
IFN
example of a gene induced by IFN-gamma and its role?
ClassII transactivator (not in MHC locus) induced by IFN-gamma to drive class II transcription
2 ways that MHC genes increase diversity?
- polymorphism
- polygeny
what is polymorphism?
many variations of MHC genes (i.e. alleles) at the same locus
what gene in MHC II is most polymorphic?
beta chains
what MHC class is the most polymorphic?
MHC I
which 2 MHC genes are less polymorphic?
HLA-DRalpha and H-2Ealpha
what is a consequence of polymorphism introducing many alleles for MHC I and MHC II?
unlikely to be homozygous –> therefore can present many Ag
what is a haplotype?
given combo of MHC alleles on 1 chromosome
what is polygeny?
many copies of a gene is possible
describe the type of dominant expression of MHC alleles
codominant –> all expressed at same time
evolution of MHC
MHC co-evolves with pathogens
2 types of polymorphism
- polymorphism within a population
- polymorphism within an individual
what is the name for polymorphism within a population?
Negative Frequency Dependent Selection
what is negative frequency dependent selection?
puts pressure to maintain rare alleles
why do we want to keep rare alleles?
pathogen can mutate to evade allele that is common, but then rare allele gives resistance –> keeps us unpredictable
what is the name for polymorphism within an individual?
heterozygous advantage
allelic variations lead to different _______ of MHC
allelic variations lead to different isoforms of MHC
how many aa can be different btwn MHC isoforms?
up to 20 aa different
what is different btwn MHC isoforms?
structure is unaffected, just the peptide binding cleft is affected
what part of the peptide binding cleft is different btwn MHC isoforms?
anchor residues
is it possible for Ag processing not to generate peptides that bind our MHC?
yes if homozygous –> fewer peptides can be presented (common in inbred animals)
in which instance can it be useful to predict peptide anchor residues?
vaccine design –> peptide anchor residues that allow for improved presentation will increase immune response
what is the consequence of MHC isoforms having diff anchor residues?
can bind diff peptides
what is required for TCR to be stimulated?
- matching MHC
- matching antigen
what is alloreactivity?
primary T cell response against allelic variants of MHC in the species
what occurs in direct allorecognition?
non-matching MHC is presented to T cell –> no restriction so will mount T cell response
what occurs in indirect allorecognition?
matching MHC presents non-matching MHC as its peptide to T cell –> presented by correct MHC and will induce T cell response
what are MHC congenic mice?
genetically identical except at MHC locus
what do MHC congenic mice allow for? (2)
- to compare biological effect of diff alleles in the same genetic background
- compare effect of given allele in diff genetic backgrounds
assay to determine alloreactivity?
mixed lymphocyte reaction (MLR)
describe MLR
irradiated/mitomycin-C treated donor cells containing T cells and APC
+
recipient CD4 T cells
if proliferation of CD4 T cells –> there was allogenic reaction allowing TCR to be activated
what are super antigens?
antigens that bind independently to MHC and TCR –> don’t need to be processed and don’t bind peptide binding cleft
describe specificity of T cell response by super antigens
not peptide-specific response –> does not prime Ag specific T cells
describe T cell response by super antigens?
drives massive cytokine production by CD4 T cells
how do super antigens work?
stable MHC presenting a peptide and non-matching TCR are brought together by the super antigen
2 reasons why MHC-encoded class 1B genes are not like other MHC-encoded genes?
- not polymorphic
- don’t all interact with T cells
what are MHC-encoded class 1B genes involved in?
involved in innate immunity –> interact with NK cells
characteristics of ligands of non-MHC encoded class 1B genes?
some don’t have ligands, ligands can be non-peptidic
example of non-MHC encoded class 1B gene
CD1
CD1 vs MHC-encoded gene
genetically identical except for the MHC locus
role of CD1
presents non-linear LIPID ligands to T cells
CD1-restricted T cells vs other T cells
CD1-restricted T cells don’t express CD4 or CD8
What is CD1 recognized by?
invariant NK T cells
why is the CD1 recognition process considered to be btwn innate and adaptive immunity?
innate –> presents diff lipids from many organisms
adaptive –> NK T cell has fully rearranged TCR
3 main APCs
- DCs
- macrophages
- B cells
ANTIGEN UPTAKE
- DCs
- macrophages
- B cells
1/2. DCs/macrophages –> macropinocytosis and phagocytosis
- antigen-specific BCR
MHC EXPRESSION
- DCs
- macrophages
- B cells
- DCs –> MHC low on tissue-resident DCs, high on lymphoid DCs
- macrophages –> MHC inducible by bacteria and cytokines
- B cells –> MHC is constitutive but increases when activated
CO-STIMULATION
- DCs
- macrophages
- B cells
- DCs –> inducible, high on lymphoid DCs
2/3. macrophages/B cells –> inducible
LOCATION
- DCs
- macrophages
- B cells
- DCs –> ubiquitous thru body
- Macrophages –> lymphoid tissue, connective tissue, body cavities
- B cells –> lymphoid tissue, peripheral blood
main role of APC for DCs
T cell priming and expansion
main role of APC for macrophages and B cells
to get recognized by CD4+ T cell to get activated
describe movement of DCs and what allows them to be motile
inflammation allows them to deliver Ag to lymphoid tissue from site of infection
immature DCs vs mature DCs
immature –> highly phagocytic
mature –> high MHC II expression
how do APCs get activated? (3)
- receptors (PRR, BCR)
- tissue damage
- inflammatory cytokines
why are DCs, macrophages, and B cells the only cells that can activate naive T cells?
they have the necessary costimulatory molecules
DCs are the main drivers of….
DCs are the main drivers of clonal expansion and T cell differentiation
where are DCs located in the lymph nodes?
throughout the cortex, in T cell zones
what antigens can DCs present?
basically any type
where are macrophages located in the lymph nodes?
throughout lymph nodes (in marginal sinus) close to afferent and efferent lymphatics
main role of DCs
prime T cells
what type of antigens do macrophages present?
bacterial Ag
what type of T cells do macrophages interact with?
primed T cells
where are B cells found in the lymph nodes?
in the follicles
what type of antigen do B cells present?
soluble Ag
what type of T cells do B cells interact with?
B cells interact with primed T cells via BCR
B cells and toxins
B cells can also neutralize toxins
2 types of DCs
- conventional DC
- plasmacytoid DC
where are conventional DCs found?
under surface epithelia and solid organs with IMMATURE phenotype
when mature, what do conventional DCs express?
MHC II and co-stim molecules to activate naive T cells
where are plasmacytoid DCs found?
in blood and lymphoid tissue
what do plasmacytoid DCs secrete?
type 1 IFN
role of plasmacytoid DCs
poor at priming T cells bc has fewer co-stim molecules but has TLRs for sensing VIRAL infection
5 ways that conventional DCs process/present Ag
- receptor-mediated phagocytosis
- macropinocytosis
- viral infection
- cross-presentation after phagocytic/macropinocytic uptake
- transfer from incoming DC to resident DC
RECEPTOR-MEDIATED PHAGOCYTOSIS
- pathogen type
- MHC type
- T cell type
- extracellular bacteria
- MHC II
- CD4 T cells
macropinocytosis
- pathogen type
- MHC type
- T cell type
- extracellular bacteria, soluble antigens, virus particles
- MHC II
- CD4 T cells
VIRAL INFECTION
- pathogen type
- MHC type
- T cell type
- viruses
- MHC I
- CD8 T cells
CROSS-PRESENTATION AFTER PHAGOCYTIC/MACROPINOCYTIC UPTAKE
- pathogen type
- MHC type
- T cell type
- viruses
- MHC I
- CD8 T cells
TRANSFER FROM INCOMING DC TO RESIDENT DC
- pathogen type
- MHC type
- T cell type
- Viruses
- MHC I
- CD8 T cells
What are langerhans cells?
immature conventional DC in the skin
role of langerhans cells
highly phagocytic –> transfer skin Ag to mature DC in lymph node
what allows langerhans cells to migrate?
Ag capture
what activates DCs in tissue?
TLR signaling
what happens once DCs have been activated by TLR signaling?
LICENSING: chemokine receptor (CCR7) expression is increased
what happens once the DC has been licensed?
MIGRATION: CCR7 binds CCL21 ligand binding on lymphoid tissue for migration AND maturation
what happens once the DC matures?
morphology changes so they become less efficient at phagocytosis and increase MHC and co-stim molecules
what co-stim molecules are increased in mature DCs?
B7.1 and B7.2
what is reduced in mature DCs?
MARCH1
why is MARCH1 reduced in mature DCs?
to allow for increased MHC I stability for better Ag interaction
