T Cell and B Cell Activation and Signaling Flashcards
To activate naive T cells
- TCR
- Costimulatory
- Cytokine signaling
CD4+ T helper cells antigen interaction
Via TCR with antigen peptide complexed with class II MHC on antigen presenting cell
CD8+ T cytotoxic cells antigen interaction
TCR interaction with antigenic peptide bound to class I MHC on target cell
CD4+ T helper cell activation
Essential for development of cell-mediated immunity and optimal humeral immunity
TCR receptor signaling
Engagement by peptide/MHC initiates multiple pathways
Regulated by activation/inhibition of protein kinases/phosphatases and amplified by cascades
Costimulatory signaling
CD28 interacting with B7 family members (CD80/CD86) on antigen presenting cells
Acts synergistically with TCR signaling to enhance gene transcription and stabilize cytokine mRNA
Cytokine signaling
Antigen presenting cell makes cytokines or autocrine signaling (to provoke making of transcription factors)
Immediate gene expression
Within 30 min of TCR signaling
ie. TF
Early gene expression
1-6h of TCR signaling
ie. Cytokines
Late gene expression
More than 2 days after TCR signaling
ie. Adhesion molecules
IL-2
T cell growth factor
Allows autocrine growth, cell cycle progression and differentiation into memory and effector cells
GM-CSF
Neutrophil production
First line of defence against bacteria
Major events of TCR signaling
Phospholipase Cgamma activation Increase in intracellular Ca concentrations Protein kinase C activation Nuclear translocation of NFkappaB Activation of Ras/MAPK pathway
Receptors/AP involved in TCR signaling
TCR/CD3 complex, CD4, CD8 coreceptors
Accessory molecules CD2, CD28, CD45
CD45
(T cell signaling)
Cell surface phosphatase that catalyzes the dephosphorylation of inhibitory tyrosine residue on p56lck
Causes activation and phosphorylation of CD3 ITAMs and phospholipase Cgamma
Calcium release
Ca released with 1 TCR
Max release with 10+ TCR
p56lck
(T cell signaling)
CD4/CD8 associated protein tyrosine kinase
Sequestered into lipid rafts (that exclude TCR/CD3) in resting T cell
TCR engangement recruits TCR/CD3 complex into lipid rafts and CD4/CD8 coreceptors that interact with invariant regions of the MHC molecule form clusters
Phosphorylates the ITAMs located on 4 chains of CD3 complex
SMAC
Central and peripheral
Immunological synapse formed by sequestering TCR/CD3 into lipid raft
TCR/CD3 complex molecules on the inside and adhesion molecules on the outside
pSMAC
CD2 on T cell interacting with LFA-3
LFA-1 on T cell interacting with ICAM-1
cSMAC
TCR/CD3 interacting with MHC
p56lck
CD4/CD8 interacting with MHC
ITAMs (T cell)
Located on zeta, gamma, delta and epsilon chains of the CD3 complex
zeta Chain of CD3
(T cell signaling)
Phosphorylated by p56lck
Homodimer forms docking sites for protein tyrosine kinase ZAP70, which memes activated
ZAP70
(T cell signaling)
Associated with zeta chain of CD3 to become activated
Phosphorylates membrane associated adaptor proteins (Vav1, Shc, LAT, SLP76) that act as scaffolds for the recruitment of other molecules in signal transduction
Vav1
(T cell signaling)
Membrane associated adaptor protein that acts as scaffold for recruitment of other molecules in signal transduction
Phosphorylated by ZAP70
Shc
(T cell signaling)
Membrane associated adaptor protein that acts as scaffold for recruitment of other molecules in signal transduction
Phosphorylated by ZAP70
LAT
(T cell signaling)
Membrane associated adaptor protein that acs as scaffold for recruitment of other molecules in signal transduction
Phosphorylated by ZAP70
Phospholipase Cgamma docks and becomes phosphorylated and activated
SLP76
(T cell signaling)
Membrane associated adaptor protein that acs as scaffold for recruitment of other molecules in signal transduction
Phosphorylated by ZAP70
Phospholipase Cgamma
(T cell signaling)
Docks to LAT and becomes phosphorylated/activated
Hydrolyzes membrane associated phosphoinotisol bisphosphate to generate IP3 and DAG
Ionistol 1,4,5-triphosphate (IP3)
(T cell signaling)
Result of hydrolysis of phosphoinotisol bisphophate by phospholipase Cgamma
Causes Ca released from ER
Causes opening of Ca channels in cell membrane
NFAT
(T cell signaling)
Dephosphorylated by calcineurin, which is activated by increase Ca levels caused by IP3
NFAT translocated to the nucleus where it causes transcription of cytokines including IL2 and IL4
DAG
(T cell signaling)
Byproduct of hydrolysis of phosphoinotisol bisphosphate by phospholipase Cgamma
Activates PKC
Protein kinase C
(T cell signaling)
Activated by DAG
Translocates to lipid rafts
Phosphorylates serine and threonine residues
Initiating cascade of signaling events that cause activation of NFkappaB
NFkappa B
(T cell signaling)
Usually kept inactive by IkappaB
Activation of IKK allows phosphorylation of IkappaB causing NFkappaB
Promotes transcription of IL2
RAS
(T cell signaling)
Small G protein
Activated by GTP following TCR-CD3 signaling
Leads to activation of MAPK pathway, including MAPK ERK
ERK
(T cell signaling)
Activated by Ras activated MAPK pathway
Activates transcription factor Elk that induces Fos expression
Phosphorylates Fos, which combines with Jun to form transcription factor AP1 involved in regulating IL2 gene transcription
AP1
(T cell signaling)
Phosphorylated Fos + Phosphorylated Jun
Involved in regulating IL2 gene transcription
CD28
Present on surface of resting and activated T cells as disulphide linked homodimer
Interacts with B7 family members from APC
B7 family
B7-1 (CD80) and B7-2 (CD86)
Found on dendritic cells, activated macrophages and activated B cells
Cytokine mRNA
Usually very unstable to regulate inappropriate immune response and potential auto reactivity
Negative Costimulatory signaling
Only in activated T cells Using CTLA4 (CD152)
CTLA4
Found only on activated T cells
Structurally similar to CD28, binds to B7 family members but provides inhibitory signal to down-regulate T cell activation
Induced within 24h of TCR engagement and has a higher affinity for B7 molecules than CD28
Expression is proportional to strength of CD28 signalling, allowing for correct amount of regulatory braking
PD-1
Interacts with PD-L1 and PD-L2
Inhibits T cell activation
B cell signaling
mIg engagement and cross linking by antigen
Initiates Src kinase, which phosphorylates ITAMs of Ig-alpha and Ig-beta
ITAMs are docking sites for Syk
Src kinase
(B cell signaling)
Initiated by cross linking of mIg of B cell with antigen
Phosphorylates ITAMs of Ig-alpha and Ig-beta
ITAMs are docking sites for Syk
Syk
(B cell signaling)
Phosphorylated by docking on ITAMs of Ig-alpha and Ig-beta
Phosphorylates adaptor protein BLK
BLK
(B cell signaling)
Phosphorylated by Syk
Docking site of PLCgamma2 and Bruton’s tyrosine kinase (BtK)
Causes induction of multiple signaling pathways that culminate in the activation of transcription factors
B Cell coreceptors
Complex of CD19, CR2 and TAPA-1
CD19
Part of B cell coreceptors
Long cytoplasmic tail that has docking sites of intracellular molecules, such as PTK lyn
Lyn
Protein tyrosine kinase
Augments signals delivered by the BCR
CR2
Part of BC coreceptors
Interacts with C3d
C3d
Formed by C3b cleaved by Factor I
CD22
Part of BC coreceptors
Constitutively associated with BCR
Following activation, delivers negative signal due to tyrosine phosphatase SHP-1 bound to ITIM
SHP-1
Bound to ITIM on CD22
Delivers negative signal following activation of BCR
ITIM
On cytoplasmic tail of CD22
Binds SHP-1
Clonalanergy
State of unresponsiveness
CD4+/CD8+ T cells that receive signal through TCR/CD3 complex that fail to receive costimulatory signal
Unable to respond to antigenic peptide
Alterations in key components of TCR signaling pathways
