Immune Receptors And Signaling Flashcards
Src kinases are associated with the ______ family of integrin-linked receptors
FAK
[non-tyrosine kinase]
What are the 5 major categories of receptors?
Integrins RTK (EGF) Glucocorticoids Chemokines Delta notch
What is the primary issue with a CD40 or CD40L deficiency?
T-cell isotype switching
What is the primary issue of CD3y deficiency?
No T-cell development = early-onset SCID
What is the primary issue with a CD8 deficiency?
Inability to eliminate EBV (or other viral infections)
What is the primary issue with a ZAP-70 deficiency?
Recurrent infections, poor survival after 2 years of age
Activating immune receptors have separate polypeptide chains for recognition and associated signaling polypeptide chains, which contain cytosolic ________
ITAMs
[immunoreceptor tyrosine-based activating motifs]
Inhibitory receptors in the immune system have ______ on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition
ITIMS
[immunoreceptor tyrosine-based inhibitory motifs]
The inhibitory receptor ______ is found on B cells and myeloid cells
FcyRIIB
What is the IgE receptor containing ITAMs?
FceRI
True or false: the TCR complex consists of the alpha/beta TCR covalently linked to the CD3 and zeta proteins
False - they are NON-covalently linked
The association of the TCR with CD3 and zeta are mediated by _________ residues in their transmembrane regions
Both TCR alpha and beta have carboxyl-terminal _________ tails that are 5-12 aa long
Charged
Cytoplasmic
Can the alpha/beta TCR chains transduce signals?
No, the cytoplasmic regions are too small to transduce signals, so CD3 and zeta proteins serve as signal-transducing subunits of the TCR complex
How do ITAMs serve as signal transducers?
They are the regions of signaling proteins that are phosphorylated and dock other signaling molecules, like zap70
Which 3 portions of the APC-T cell interaction perform signal transduction?
CD4 (or CD8)
CD3 and zeta chains with ITAMs
CD28 (binds B7-1/B7-2)
Which portion of the APC-T cell interaction functions in antigen recognition?
TCR (binds class I or II MHC)
Which portion of the APC-T cell interaction functions in adhesion?
LFA-1 (binds ICAM-1 on APC)
CD3 is composed of 3 polypeptide chains arranged in what 2 pairs?
Gamma-epsilon
Delta-epsilon
Describe the structure of the CD4 coreceptor
4 extracellular Ig-like domains
Hydrophobic transmembrane region
Highly basic cytoplasmic tail 38 amino acids long
Describe the structure of the CD8 coreceptor
Two related chains: CD8-alpha and CD8-beta
Both chains have single extracellular Ig domain, a hydrophobic TM region, and highly basic cytoplasmic tail about 25 aa long
CD8 binds mainly to ______ MHC molecules, and also interacts with _____________
Class I
B2 microglobulin
What is one of the most important docking proteins that connects CD4-Lck to the ITAM motif of the TCR complex in an Ag activated T cell?
ZAP-70
PLC signaling is important in immune signal transduction. It requires ______ adaptor protein to dock to the membrane
LAT
PLC activation –> increased cytosolic ____ –> calcineurin –> _________ transcription factor
Ca2+
NFAT
PLC activation –> _______ –> PKC –> _______
DAG
NFkB
The MAPK signaling pathway involving Ras and ERK or JNK results in what immuno transcription factor production?
AP-1
Also comes from PI3 kinase –> PIP3 –> akt, mTOR
The Src family, Syk family (Zap-70), and Tec family, all belong to which major family of signaling proteins?
Non-receptor tyrosine kinase families
LAT is an integral membrane protein that functions as an adaptor.
What is the purpose of adaptors in T cell activation?
Adaptors serve as molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules
What is the adaptor protein for T cells vs. B cells?
T cell adaptor = LAT
B cell adaptor = BLNK
What is the mechanism of action of Cyclosporine?
Uses phosphorylated tyrosine as docking site, resulting in similar Ca signaling to PLC activation
Inhibits the TF NFAT and IL-2 gene expression downstream of PLC
What is the overall end goal of Ras-MAP kinase pathway activation?
IL-2 expression (AP-1 is the TF, but we want to make IL-2)
In the Ras-MapK pathway:
The Lck activates ______ upon Ag recognition
This phosphorylates adaptor protein _____
This binds ______ adaptor, which docks GTP/GDP exchange factor _______.
That exchange factor converts Ras-GDP to Ras-GTP, which activates ____ kinase and _____
Leading to activation of AP-1
ZAP-70
LAT
Grb-2; SOS
MAP; ERK
Multiple signaling pathways converge in Ag-stimulated T cells leading to transactivation of the IL-2 gene
________-________ activates NFAT, and Ras and Rac pathways generate _______.
PKC is important in activating ______, which is a p50p60 heterodimer inactivated by IkB
Calcium-calmodulin; AP-1
NFkB
____ and ___ are the primary TFs that regulate IL-2 gene expression
AP-1; NFkB
Describe general activation of NFkB
NFkB exists bound to IkB (inhibitor) in cytoplasm
When TCR is activated by Ag, IkB dissociates and NFkB translocates to the nucleus for transcription
The BCR is a TM form of an Ab molecule associated with 2 signaling chains: Ig-alpha and Ig-beta. These are ________ -linked to one another and non-covalently associated with the BCR.
Ig-alpha and Ig-beta contain ____ in their cytoplasmic tails which mediate their signaling functions
Disulfide
ITAMs
Signaling via the BCR complex requires ITAMs, which activate _____-_____, leading to activation of PLCy and Ras+Rac GTPases, which are followed by NFAT, NFkB, and AP-1
Src-Syk
When PLCy and Ras are activated during BCR signaling, they turn on genes involved in what 3 general processes?
Cell growth
Differentiation
Survival
[also involved in complement]
The role of complement in B cell activation involves ____ and ____ kinases.
A microbe with bound _____ can then bind to the ____receptor in the BCR complex
Src; PI3
C3d; CR2
Why is inhibitory signaling important in the immune system?
Limit collateral damage to host
Prevent uncontrolled inflammation and lymphoproliferation
Prevent reactions against self
Inhibitory signaling in lymphocytes is mediated primarily by inhibitory receptors and also by enzymes known as ______ _______ _______
TLR signaling stimulates expression of proteins called ______. _____ is an important cytokine in this process.
E3 ubiquitin ligases
SOCS; IL-1
Inhibitory receptors typically recruit and activate ________ that counter signaling events induced by Ag receptors
Phosphatases
What cell types are inhibitory receptors especially important for?
NK cells
T cells
B cells
[as well as other cells of innate immunity]
An inhibitory receptor has an EC ligand-bindng domain and a cytosolic ITIM motif.
Ligand binding results in phosphorylation of the ITIM tyrosine by a ____ family kinase
The phosphorylated ITIMs recruit an ____ domain containing tyrosine phosphatases that can attenuate immune receptor signaling
Src; SH2
What are the coreceptors for TCR signaling and what are their roles?
CD4 and CD8; increase ITAM phosphorylation
What is the coreceptor on B cells and what does it do?
Complement Receptor 2 (CR2/CD21); increases ITAM phosphorylation, can also bind C3d in complement
What is the inhibitory receptor associated with T cells?
CTLA-4 (CD28)
What are the 2 inhibitory receptors in B cells?
CD22 and FcyRIIB
CD28-CD80/86 costimulation in activation of T cells - ______ receptor
B7
Receptors for different cytokines are classified into families on the basis of conserved extracellular domain structures and signaling mechanisms. What are the 5 cytokine receptor families?
Type I cytokine (hematopoietin) Type II cytokine TNF receptor family IL-1 receptor family 7-TM GPCR receptors
Which cytokine receptor families utilize JAK STAT signaling?
Type I and Type II
SCID is associated with what cytokine/cytokine receptor family?
IL-7 which is a ligand for Type I cytokine (hematopoietin) receptors
Which cytokine receptor family is associated with TLRs?
IL-1 receptor family
Which receptor family includes the ligands TNF-alpha and TNF-beta?
TNF receptor family
What are the ligands for the GPCR receptor family?
Chemokines
JAKs and STATs are the key players in type I and II cytokine receptor signaling
JAKs phosphorylate _________ on STATs, which are ______ transcription factors.
The stats then dimerize and translocate to the nucleus to induce the expression of genes.
They bind directly to the _______ sequence, and can be attenuated by ____ _________.
tyrosine; latent
Promoter; E3 ligases
What are the 3 potential results of TNF receptor signaling?
NFkB activation
MAP kinase activation
Induction of apoptosis
Ligation of the TNF-RI results in recruitment of adaptor protein ______ which in turn activates TRAF (E3 ubiquitin ligases) and the RIP1 kinase
TRADD
Which receptor family involves IRAKs linking adaptors to TRAF6, an E3 ubiquitin ligase required for NFkB activation?
IL-1 receptor family
[IL-1R signaling also includes MapK activation and phosphorylation of IRF3 and IRF7, inducers of Type I interferon transcription]
______ deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency in an autosomal recessive manner
ADA (adenosine deaminase)
What are the most common symptoms associated with an ADA deficiency?
PNEUMONIA
Also chronic diarrhea and widespread skin rashes
What is the link between ADA deficiency and lung issues?
Adenosine can act as a signaling molecule in hypoxic environments, such as that found in inflamed lungs (serves regulatory role in chronic lung disease)
Lung adenosine levels accumulate in association with increased lung inflammation and damage
What is the most common form of SCID?
X-linked SCID (note more common in boys than girls)
What mutation is associated with X-linked SCID?
Mutation in the common y-chain subunit of cytokine receptors
[deficiencies in many cytokine signals, but IL-7 affects defects in T cell development –> reduced T cells but normal B cells, IL-15 defects –> deficiency in NK]
What disease results in a failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells?
X-linked agammaglobulinemia (Bruton agammaglobulinemia)
When does XLA first become apparent?
Usually not until 6 mos of age, when maternal Ig becomes depleted
What are common symptoms associated with XLA?
Recurrent bacterial infections of respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia
X-linked agammaglobulinemia is caused by what type of mutation?
Mutation in cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (Btk)
When it is mutated, pre-B cell receptor cannot deliver signals and maturation stops at this stage
