Lec 4: Basics of Cell-to-Cell communication Flashcards
How do immune cells communicate at a distance
Secretion fo proteins, hormones. Note here that concept of diffusion applies
Classes of Cytokine effects
soluble secreted proteins that act in an autocrine or paracrine manner
Pleiotrophy
Redundancy
Synergy
Antagonism
Pleiotrophy
induced varied responses in the target cell
Redundancy
different cytokines induce the same response
Synegry
cytokines cooperate in inducing a specific response
IFN for example (multiple can converge and boost a given signal)
Antagonism
cytokine blocks the activity of another cytokine
Why is the diversity of cytokine folds important
many conformations implies
different diffusion rates
different specificities
different regulators
what do cytokines depend on
transcription factors, signalling protiens present and epigenetic effects
why are cytokines benificial
for modulation of the immune response
Why is the redundancy of cytokines important
incase on cytokine does not work, we can maintain and immune response even with a partial loss
can boost a given signal (this is a synergistic effect and coordination)
cross talk
Why is antagonism important
what to dampen the signal at the end
also allows different tissues to react in different ways (reversal of immune response)
Can a single cytokine bind to multiple receptors
yes
what are the 5 classes of cytokine receptors
Ig-type ectodomain
TNF homotrimeric ectodomain
Cytokine Type 1 receptors (core ectodomain), can have other domains
Cytokine TYpe 2 receptors (core ectodomain), can have other domains
Chemokine receptors (typical and atypical)
Paracrine vs autocrine
Paracrine signaling: a cell targets a nearby cell (one not attached by gap junctions). The image shows a signaling molecule produced by one cell diffusing a short distance to a neighboring cell. Autocrine signaling: a cell targets itself, releasing a signal that can bind to receptors on its own surface.
Paracrine vs Autocrine
Paracrine signaling: a cell targets a nearby cell (one not attached by gap junctions). The image shows a signaling molecule produced by one cell diffusing a short distance to a neighboring cell. Autocrine signaling: a cell targets itself, releasing a signal that can bind to receptors on its own surface.
IL2 and IL15
IL2 and IL15 are essential cytokines mediating cell proliferation (IL2 is especially important in clonal expansion)
STAT5
STAT5 binds genes associated with cell proliferation, apoptosis, differentiation and inflamation
big driver of proliferation and apoptosis
How do antigen presenting cells change the flavour// activate a given T-cell
In this order
MHC
CO-stimulation (additional signal cascades)
Cytokine secretion
How are chemokines classified
divided into subfamilies on the basis of the presence of as conserved cysteine motif in their mature sequenses
are folded together by cysteine bridges
Pleiotrophic effects of chemokines
Extensive ligand promiscuity in the chemokine receptor family, and many chemokines can bind to multiple receptors
classes of chemokines
C
CC
CXC
CX3C
see slides for diagram
Typical chemokine receptors
containing a seven-transmembrane domain
G protein-coupled chemotactic receptors
conserved DRYLAIV motif (AA sequence)
cell migration
Atypical chemokine receptors (ACKRs)
predicted seven transmembrane domain structure
do not signal through G proteins and lack chemotactic activity
substitutions in the DRYLAIV domain
Signalling via beta-arrestin leads to chemokine internalization
What is the purpose of beta-arrestin signaling
Signaling via beta-arrestin leads to chemokine internalization = ANTAGONISM
ligand scavenging and degredations
chemokine trafficking
control inflammatory and immune responses
nomenclature for typical chemokines receptors
CCL and CXCL
nomenclature for Atypical chemokines receptors
ACKR
how do atypical chemokine receptors help control infammation
they help to trap excess chemokine
erythrocytes can act as a buffer for excess serum chemokines
protection against excessive cytokine storms or chronic inflammation
Viruses can usurp cytokine signalling
some viruses encode protiens that mimic host cytokines, chemokines and their receptors
Viral mimics do not have sequence similarity to host proteins, yet possess similar function
what do you notice about the types of chemokines herpesviruse mimics
immunosupression
IL6 reduces the inflammatory response and chemokine signalling
Viralkines
Mimics cytokine, chemokine, or chemokine receptors
interupt, mimic or distrupt host signalling cascades
Ep-barr secretion of IL10 to suppress adaptive and innate immune responses
What kind of extracellular signals do cells use do communicate
Secretion of cytokines// proteins as well as hormones to induce immunocompetent (diffuses into cells)
The can also secrete exosomes
Extracellular vesicles
delivery of bioactive macromolecules
enclosed in a lipid bilayer, variable composition
can enhance or supress immune activites
Why are extracellular vesicles so important when it comes to cell signalling
They contain a ton of information abot the cell that secreted them
Surface markers, DNA, proteasome etc…
What are the two types of extracellular vesicles
exosomes and microvesicles
How does loss of integrety// secreation// membrane blebbing occur?
increase in temperature, and infection, toxins high osmotic stress etc
Necrosis// Necrotic Cell Death
aka cell lysis NOT apoptosis (dis is more violent)
membrane rupture makes apoptotic blebbs which are little packets that may be degraded
huge inflamatory response
Apoptotic bodies
Small little fragments to be eaten by macrophages
Cell contents not released, no inflamatory response
contain valuable information about the cells death
Biogeneisis of exosomes
A modified endosome, the intracellular components of these can be controlled
Derived from MBV (multivesicular bodies) which fuse with the plasma membrane and release intraluminal vesicles as exosomes
30-100nm
Biogenesis of microvesicles
generated from budding from the plasma membrane
lil scoops of a sample of the cytoplasm
30-2000nm
Dendridic cells and Extracellular vesicles
Dendritic cells may engulf important anitgens or signalling moleucles then secreate them in extracellular vesicles to a variety of immune cells
may lead to inflammatory responses and or immune cell activation
Diffusion of PRR to other cell types
activation of other non-infected cells
super important in exosomes
Exosome secretion during infection
exosomes containing antigens derived from pathogens can helpp activate the imune system through PAMPs and cross-priming DC antigen presentation
also can have immunosuppressive effects
Group cytokines and chemokines based on their strucutre and receptors
Chemokines:
cysteine bridges in 4 groups, C, CC, CXC and CX3C chemokines which can bind to either typical or atypical receptors. Chemokines exhibit extreme promiscuity when it comes to their receptors (they can often bind many)
Cytokines:
Conformationally very different which lead to variations of specificity, difffusion and regulation. They bind to 5 different types of receptors (Ig-type, TNF homotrimeric, Cytokine type 1, cytokine type 2, chemokine). Usually again, a given cytokine can bind multiple receptors
Compare and contrast the actions of cytokines and chemokines
A chemokine is a cytokine that specificaally induces motility towards a site of inflamation
Explain the importance of Cytokine-based communication in terms of pleiotrophy
here communication is important because pleiotrophy of target cell means different cells with respond differently to a given cytokine.
This is due top variations of a cells given receptors, epigenetics, proteasome, transcription factors, and constituents of the signal transduction cascade
Explain the importance of Cytokine-based communication in terms of redundacy
Redundancy is important because just incase their is a mutation, or infection or simply the cell doesn’t have a given receptor the end result will still get triggered
issa good back up plan
Explain the importance of Cytokine-based communication in terms of Synergy
Coordination, and cooperation and crosstalk to boost signals
for example, IFN signals boost each other
Explain the importance of Cytokine-based communication in terms of antagonism
Imporant when you want to silence a cascade before it gets out of control or simply because you dont what that signal in a given cell type or tissue
What is the importance of extracellular vesicles in immune communication and signalling
Allows a “controlled” diffusion of lysed cell components among the blood stream or lymph to activate immune cells (this is jsut one example = a dendritic cell).
membrane vesicles give a good idea of what happened at a given site of infection.
MAPK
A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines
