linking innate to adaptive immunity Flashcards
what are the 3 signals for activation of t cells?
1- activation: pMHC:TCR
2- survival: B7.1 or B7.2 / CD80 or CD86 :CD28
3- differentiation: cytokines
what happens with DCs when they encounter PAMPs? (4 things)
increase migration receptors expression (ex CCR7)
increases antigen processing
increases costimulatory molecules expression (not present in naive DCs)
increases MHC molecules expression
what happens with DCs when they encounter PAMPs?
increase migration receptors expression (ex CCR7)
increases antigen processing
increases costimulatory molecules expression (not present in naive DCs)
increases MHC molecules expression
what is priming?
first contact of T cell with their antigen
what are 3 characteristics of unactivated/immature DCs?
many dendrites
can phagocytose
located in peripheral tissue
what are characteristics of activated DC in lymphoid tissue?
express MHC peptide and costimulatory molecules
interacts with T cell
what are characteristics of conventional DCs?
travel to lymphoid tissue once activated
activate T cells in lymphoid tissues
conventional/professional APC
what are characteristics of plasmacytoid DCs?
high PRRs levels
can produce large amounts of type I IFN
stay at infection site
secrete cytokines that amplify local response
what happens to T cell once it is activated by DC?
proliferation
name 3 types of lymphoid tissues
lymph nodes, spleen, peyer’s patch
through what structures do DCs and T & B cells enter and exit lymph nodes?
DCs enter via afferent lymphatics
T & B cells enter via high endothelial venules HEV and exit via efferent lymphatics
what happens if antigens from virus kills the DC?
DC transfer antigen to resident DC or cDCs
how long do lymphocytes spend in secondary lymphoid organs? why?
they spend hours trying to find their antigen match and return to circulation if they don’t
what do T cells become once they are activated and proliferate?
effector T cells
where do PRRs get activated?
in periphery tissue
what are the 4 stages of T cell entry into the lymph node
rolling, activation, adhesion, diapedesis
what are adhesion molecules and chemokines involved in T cell entry in lymph node?
selectins
CCL21 (chemokine binding to CCR7)
integrin
what is each adhesion molecule’s role?
selectins: rolling adhesion to HEV & targetting to lymphoid tissue
chemokines: activation
integrin: arrest and adhesion
what can DCs secrete to attract T cells?
chemokines
what are fibroblastic reticular cells? what can they do?
cells that provide roadways for naive T cells and secrete CCL21 chemokines to help attract T cells and DCs to lymph nodes
what happens when T cells find their Ag match?
they stop moving and commit to a 8 hours or longer relationship with DC
for how long can T cells experience proliferation and differentiation?
for 4 days! what causes inflammed lymph nodes
where do T cells arise from
arise in thymus from bone-marrow progenitors
what do T cells recognize?
antigen peptide fragments bound to self molecules of MHC
what does MHC stand for and where are they expressed?
Major Histocompatibility Complex. expressed on APCs membrane
what do CD stand for
clusters of differentiation
what are the 2 types of T cells
CD8+ (cytotoxic T lymphocytes)
CD4+ (Helper T cells - TH1, TH2, TH17, Treg, TFH)
what do each type of T cells recognize?
CD4+ recognizes Ag on MHC II
CD8+ recognizes Ag on MHC I
what influences what type of effector T cell will arise
the PAMP that activated DC which influences the type of cytokines produced -> leads to type of effector T cell
where do DCs get activated?
in the lymph nodes
what is CCR7?
a chemokine receptor
what tissues have receptors for selectins?
HEV and mucosal epithelium
Does T cell - Ag encounter in lymph node always lead to activation?
no: sometimes the DC dies or else
what kind of synapses does T cell-APC interaction form?
immunological synapse (long-term interaction)
what is contained in the TCR complex?
TCR, CD3, zeta chain, and ITAM motifs
what are ITAM motifs and where are they located?
Immunoreceptor tyrosine-based activation motif. Located on intracellular chains of CD3 and zeta chain.
When are we going to find clonotypic TCRs?
when a TCR gets activated and clones itself (otherwise all TCRs are different)
how can we have so many different adaptive immune receptors (BCRs, TCRs)?
DNA rearrangement of variable, diversity, joining, and constant genes
each chain of a TCR has which domains?
alpha chain: V, J and C domains
beta chain: V, D, J, and C domains
each domains have so many copies of each except which?
there’s only 1 constant region
what are professional APCs?
conventional DCs, macrophages, activated B cells
what are professional APC’s characteristics
express MHC class I AND class II molecules.
Express costimulatory molecules when activated.
what are non-professional APCs?
all cells expressing MHC class I under normal conditions (therefore all nucleated cells)
what type of peptide does each type of MHC present?
MHC class I = endogenous peptides (intracellular/cytosolic)
MHC class II = exogenous peptides (extracellular origin)
what is an MHC class I molecule made of?
MHC class I = 3 domain big TM alpha chain + 1 non-covalently bond constant beta2 microglobulin
what is an MHC class II molecule made of?
TM alpha + TM beta chain that have 2 domains each
apart from the alpha and beta chains, what do MHC class I and II require to be expressed stably?
peptide
what are Ig-like domains? what stabilizes it
immunoglobulin-like; domain of aprox 100 aa with alpha helices, beta strands, stabilized by an intrachain disulfide bond
what differences are found in MHC’s peptide-binding cleft?
allele-specific differences
where are IG-like domains found?
on each MHC chain
what are coreceptors? why are they there?
CD4 and CD8 molecules in T cell membrane. attach to MHC constant region to increase affinity of binding
and
initiate TCR signaling (signal 1)
what is CD4’s structure?
single chain with 4 Ig-like domains
where are Ig-like domains found?
on each MHC chain (and on CD4 and CD8 chains)
how do endogenous pathogens enter the cells?
present their HA/NA molecules to cell’s membrane receptors
or
enter with help from CD4 and coreceptor
what are proteasomes?
protease complexes that degrade polyubiquitinated proteins (antigen peptides) in the cytosol
what type of peptides are presented on MHC class I?
endogenous peptides and self-peptides
what is calnexin?
chaperone that holds MHC I alpha chains until beta2 microglobulin binds
what chaperones help beta2 microglobulin interact with MHC I alpha chain?
calreticulin, ERp57
what is TAP?
protein bound to MHC I by tapasin that pumps peptide fragments from the cytosol to the ER
what is ERAAP function?
trims peptides in ER that are too long to bind MHC I
what allows MHC to be properly folded?
peptide binding to groove
what happens once the peptide binds to MHC?
pMHC-I is released from TAP and goes to cell membrane
where are exogenous peptides fragments generated?
from internalized antigens in endocytic vesicles (endosome fused with lysosome)
what happens in APCs at the same time as exogenous peptide degradation?
production of MHC class II molecules in the ER
how are proteases degrading exogenous peptides activated?
by acidification of endosome when it fuses with phagosome
what is the invariant chain?
chain that binds to MHC class II groove to transport it from ER to endocytic vesicle.
also prevents peptides from binding to MHC II too early in the ER.
what is CLIP?
class-II associated invariant chain peptide: what becomes the invariant chain after it gets degraded by proteases in endocytic compartments
what causes the cleavage of li in endocytic vesicles?
acid pH
what is HLA-DM?
Human Leukocyte antigen-DM: releases CLIP from MHC II in endocytic vesicles
what is cross-presentation?
exogenous antigens are redirected to the endogenous presentation pathway (MHC I)
broadly how does cross-presentation work?
CD4+ T cells give permission to DC to redirect the exogenous Ag to CD8+ T cells.
DC presents exogenous Ag on MHC I to CD8+ T cells
what is required for cross-presentation?
activated CD4+ that license DC
what is hypothesized to be the “license” in cross-presentation?
IL-2 cytokine
what are autophagosomes?
vesicles that fuse with lysosomes to degrade cytosolic and exogenous peptides and present them to MHC II
what is “the digestion and breakdown by a cell of its own organelles and proteins in lysosomes?”
autophagy
how is T cell response restricted?
MHC restriction: T cell can only recognze a specific peptide when it is bound to a specific SELF MHC molecule
can an animal of a specific strain respond to an Ag on a different animal’s strain APCs?
no
what is an allogeneic MHC molecule?
a non-self MHC molecule
what % of T cells can respond to allogeneic MHC molecules? what is this phenomenon called?
1-10%
allorecognition
what does allorecognition cause related to grefs/transplants?
rejection of transplanted organs
what is an allele LOL
a specific form of a gene
what genes encode MHC molecules? where are they found?
HLA (human leukocyte antigen) genes on chromosome 6
different HLA genes code for different what?
for different MHC class alpha domain!
(ex MHC class I genes include HLA-A, HLA-B, HLA-C, and MHC class II genes include HLA-DR, HLA-DQ, HLA-DP, …)
what part of MHC I is not encoded by many alleles?
beta 2 microglobulin
what is polymorphism vs polygeny?
polymorphism: multiple alleles for each gene (ex HLA-A1 and HAL-A581)
polygene: individual has many copies of genes with the same function (ex HLA-A, HLA-B, HLA-C)
what is a haplotype in MHC context? how many do we inherit?
a particular combination of MHC alleles on a single chromosome. we inherit one from each parent
Which inherited MHC genes are expressed in offspring cells? why?
one maternal haplotype and one paternal haplotype -> get the most combinations to be able to present the most AGs
can there be an organ transplant between siblings?
it will probably still be rejected because even siblings
can there be an organ transplant between siblings?
it will probably still be rejected because even siblings inherit different combinations
what makes transplantation difficult?
human are heterozygous (except very rare exceptions)
how many MHC I alleles do you inherit from each parent?
3 (HLA-A, HLA-B, HLA-C)
where are the differences between alleles located?
on peptide binding groove. In MHC II, usually on the beta chain
when is a transplant successful?
if the recipient has the allele(s) of the donor
what are the two type of receptors we learned about?
intrinsic kinase activity
extrinsic kinase activity (kinase is noncovalently associated with the receptor)
how do receptors with intrinsic kinase activity work?
downstream signaling is initiated by dimerization and transphosphorylation
how do receptors with extrinsic kinase activity work?
downstream signaling is initated by recruitment of kinase and dimerization, followed by transphosphorylation
what is SH2?
a domain in receptor that has selective binding properties for phosphorylated tyrosine on other proteins
what do phosphorylated tyrosine do?
they’re just binding sites for a number of protein-interaction domains
how are multimolecular complexes made?
can form around adaptor proteins
what are phosphatases?
proteins that dephosphorylates other proteins
what is Lck and what does it do?
extrinsic co-receptor-associated kinase that phosphorylates ITAMs in the TCR upon co-receptor binding with Ag:MHC
what does phosphorylation of ITAMs trigger?
activation of Zap-70 which activates many downstream signaling molecules, leading to TFs
what are positive costimulatory receptors?
CD28: facilitates activation
what are negative costimulatory receptors?
CTLA-4, PD-1: help turn off activation for regulation
what is an anergic T cell? in what context do we find them?
a non responsive T cell. in absence of costimulation
what are CD28 characteristics? (3)
- EXTRINSIC TM homodimer glycoprotein
- present at baseline
- binds B7.1 and B7.2 (CD80/86) on activated APCs
what does CD28 binding to B7 trigger?
phosphorylation of CD28 -> recruitment of kinase -> additional signaling
why is it good that T cells become anergic?
decreases the probability of autoreactive T cells
what is caused by signal 1 and 2 on T cells (broadly)
IL-2 and IL-2Ralpha transcription -> secretion -> proliferation
what is IL-2?
an autocrine cytokine that bind on receptor on same cell and induces proliferation signal
what type of cell populations come from IL-2 induces proliferation?
memory and effector clonal cells
what is the other name for IL-2Ralpha? what is it?
CD25
it’s a part of the IL-2 receptor
what parts of IL-2 receptor is constitutively expressed? can they bind IL-2?
IL-2R beta and gamma. they can bind IL-2 but only weakly without IL-2R alpha
