Ch 3: Receptors and Signaling (B and T-Cell Receptors) Flashcards
Upstream
components of a signaling pathway that are the closest to the receptor
Downstream
The components of a signaling pathway that are the closest to the effector molecules that determines the outcome of the pathway
Growth factor receptors
ligand binding induces a conformational change in the receptor that results in receptor dimerization
cytoplasmic domain has tyrosine kinase activity thus, leads to reciprocal phosphorylation of cytoplasmic regions of the receptor molecules by the dimerization partener
inducible enzyme activity built into receptor
What is different about BcR and Tcr from growth factor receptors
They have very short cytoplasmic components and therefore need help from intracellular receptor-associated molecules to induce signal transduction
Iga/Igb heterodimer in B cells and Hexatriomeric CD3 complex in T cells
These are closely associated with their respective antigen receptors and are responsible for transmitting the signals initiated by ligand binding
ITAM
immuno receptor tyrosine activation motif
recurrent seqwuence motifs found on many signaling proteins within the immune system
the tyrosine becomes phosphorylated following signal transduction through the associated receptor
CD19/CD21 complex
binds to complement molecules covalently attached to the antigen
B-cells -> BcR
How do CD8 and CD4 aid in signal transduction
bind to nonpolymorphic regions of the antigen presenting MHC molecule
Lipid Rafts
Highly ordered, detergent insoluble, cholesterol and sphingolipid rich membrane regions and are populated by many molecules critical to receptor signaling
Ligand induced clusters of Bcr and Tcr move into here
immunoglobulin structure
hyper variable loose strands at the margins and a core structure of antiparallel B-sheets linked by a di-sulfide linkage
Antibody common structure
four polypeptide chains, to identical light chains and two identical heavy chains, H and L chains linked with a di-sulfide linkage and non-covalent interactions
antibody molecule forms a Y shape with two identical antigen binding regions at the tips of the Y (both H and L chains contribute to the binding domain)
Fab regions
the identical fragments that retain the antigen binding specificity of the original antibody after cleavage via papain
Fc region
the non-antigen binding region of an antibody
fragement crystalizable region
Fc receptor
on phagocytotic ot cytolytic cells or immune effector molecules
binds the antigen-coupled antibody
antigenic dererminant
a region of an antigen that makes contact with the antigen combining region on an antibody
What is the purpose of Th cells
guide the behaviour of other immune cells
Whithout them an immune response can see severely damaging due to the lack of directional cues
How does our immune system combat the use of error-prone RNA pol in mirobes
the generation of diversity
Myeloid DC’s
tissue resident and are professional APC’s
Lymphoid are the IFN secreters
Follicular DC’s
NO not act as APC’s for Th cells
Important for the maturation of B cells
What do Th1 detect for
intracellular pathogens
What do Th2 detect for
Extracellualr patogens
Treg
Can quell an immune response
CD4 and CD25
NK cells
Part of the innate immune response and do not have any antigen specific receptors
sence the absence of MHC
NKT cells
lipid and glycoproteins antigens are recognized by TcR
Express CD4
Th1 cells
secrete cytokines that promote differentation and acivation in macrophages and cytotoxic T cells
-> modulation of a cytotoxin immune response
IL-12 and IFN
induce Th1 differentation
Th2
activates B cells to make antibodies
IL-4 and IL-5
generation of Th2
Th17
promotes differentation of activated macrophages an neutrophils and support the inflammatory state
-> induced by IL-17 and IL-23
antigen activated cells
physiological changes
antigen activated cells may induce changes in their cell membranes to bear receptors for chemokines
-> only activated cells (in the lymph nodes or the spleen with migrate)
Also will bear receptors for proliferation signals such as IL2 and differentiation factors like IL4
What is Caspase 1
Cleases IL1 b/a into their mature form
part of the inflammasome
What are the gene transcripts and pathway of IL-1 activaiton
IL-1
MyD88
MAP kin
AP-1= TF leads to IL-2 secretion
What do all three types of interferon have in common
all 2 increase the expression of MHC complex proteins
What is IFNb secreated by
secreted by actived macrophages and DC’s and virus infected cells
Type 1 IFN
IFN a/b
Both are secreted by cells which have activated PRRs
a and b “interfere” by producing anti-viral ribonucleases and shutting down protein synthesis in the host cell
kills the host cell and the virus in it
Type 2 IFN
IFNg and IL10
produced by activated T and NKcells
BIases T cell help toward Th1, induces macrophages and the destruction of intracellular pathogens and differentiation of cytotoxic T cells
IL-10
type 2 IFN
secreted by macrophages as well as T, B and DC cells
Similar in structure to IFNg
Type 3 IFN
IFN lambda, IL-29, IL-28 a/b
upregulate the expression of genes controlling viral replication and host cell proliferation
TNFa
Proinflammatory
produced by activated macrophages
leads to expression of MHC and adhesion molecules
Secreted in response to infection, inflammation and environmental stressors
CD40L
Expressed on the surface of T cells and is required to signal for B cell differentaiton
Fas = CD95
binding of Fas ligand induces apoptosis when bound to its cognate receptor
Purpose of “decoy receptors”
Soluable TNF receptors exist to soak up XS TNF
the IL-1 receptor family also has this
allows fine tuning and modulation of the cytokine response. Can limit diffusion such that cytokine is only secreted and taken up effectively in a localized area
can also to prevent cytokine storms by reducing total amount of cytokine that is effectively absorbed
Why do lymphocytes express Fas on their cell surface once an infection has been cleared
TNF-R1, CD40, BAFF and April = life or death receptors
for the purpose of cell death via apoptosis
this minimizes inflammation, note that apoptosis is mediated through caspase-8
IL-17 family
proinflammatory, thus activated by NFkB -? MAP Kin -> Il-17
Released by activated T cells
Stimulates production of pro-inflammatory state
-> IL-6
as well as neutrophil mobilizing cytokines
IL-17E
is an exception to the IL-17 family
induces the Th2 response and suppresses the Th17 response
Il-6
Pro-inflammatory cytokine and anti-inflammatory mitokine
What is the general signal transduction cascade for Il-2 secretion through NFAT
PRR activation = dimerization and reciprocal phosphorylation via ITAM like domains
-> Phos = allows docking molecules to bind
BcR/ TcR clustering increases their affinity for lipid rafts
-> Lyn can then phosphorylate the iga and igb domains
(Lck does a similar thing in T cells)
PRR-> NFAT (nuclear factor activating T cells) -> activation of genes encoding IL-2 which can then modulate T-cell proliferation
PKC activates NFkB
Ikb is an inhibitor of NFkB and is bound
when a cell is activated, ikb gets Phos and is then ubiquitinated for degradation
Then NFkB can bind promoter = proinflammatory and citation events as well as the secretion of Il-2
Ras/ MAP kin
activaiton of AP-1 = TF that is important for IL-2 secretion
Ras is a G-protein
Tcell activation
Needs TcR as well as the co-receptor CD28 to be stimulated
CD28 binds CD80 on APC
leads to AP-1 activation and IL-2 secretion= cytokine
What are the 6 classes of cytokines
IL1 Hematopoietin IFN TNF IL17 Chemokine
THe IL-1 Family (general characteristics)
secreted very early in the immune response by DC’s monocytes and macrophages
stimulated by micrbes binding to PRRs
- > proinflammatory
- > induction of acute phase proteins (Type 1 IFNa/b, IL-6 and CXCL8)
Activates T and B cells and leads to the destruction of viral RNA and a general high fever to silimate temp sensitive bacteria
Members of the IL-1 family
IL-1a/b IFNa/b IL-6 IL-18 IL-33
IL-33
induction of Th2 cytokines that promote T lymphocyte interactions with B cells
Members of the Hematopoietin family (class 1 cytokines)
IL-2 IL-6 IL-4 IL12 GM-CSF, G-CSF
IL-2
leads to T and B cell proliferation
IL-6
B-cell differentation to plasma cells
IL-4 and IL12
Th cell singnalling
The JAK-STAT pathway
JAK = tyrosine kinase STAT = TF that can translocate to the nucleus
ALLOWS:
Immune specificity to cytokines
BY:
- > exquisite specificity of a given cytokine to a receptor
- > Particular cytokine receptors are bound to specific JAKs with unique STATS
- > ew Specific STAT homo/heterodimers will only interact with specific promoters
- > those promoters need to be available (not hidden in the heterochromatin)
Can be turned off by STAT inhibitors ( PIAS & SOCS)
TNFb / Lymphotoxin a
produced by activated lymphocytes
-> when binds to a neutrophil it induces adhesion and an increase in the expression of MHC
Cytokine mimicry
Epstein-Barr Virus produces an IL-10-like moleule that binds to the IL-10 receptors
-> suppresses the Th1-type cell-mediated response`
Septic shock
overproduction of TNFa and IL-1b from PRR activation -> lowers blood pressure form leaky capillaries as a result of the inflammatory response
-> cytokines that are secreted raise the body temp super high
also increases the WBC count as well as a change in respiration rate as well as blood clots and organ failure
Anti-microbial peptides
Amphipathic and net +ve
-> this allows them to interact with the acidic phospholipids of microbial membranes
C-reactive protien
an oposonin that recognizes phophocholine and carbohydrates on microbes
-> is then bound to FcR and phagocytosis is enchanced
