Exam #2 Flashcards
Complement
Group of plasma and cell surface proteins that fight invading organisms through inflammation, phagocytosis, and lysis
Mannose Binding Protein (MBP)
Binds mannose on surface of bacteria, viruses, and parasites - tags organism for phagocytosis
Activates complement pathway
C-reactive Protein
Binds to bacterial surface, acts like opsonin (binds to an Ag to promote phagocytosis)
Activates complement
IL-10
Inhibits macrophage activity
IL 12, 18, 23
Stimulate NK cells to produce IFN-γ
IFN-α and β
Stimulate NK cells and promote class I MHC expression
IFN-γ
Produced by NK cells, activates macrophages
TGF-β
Stimulates macrophages
MHC
Major histocompatibility complex - display antigens
Class I MHC is associated with which responsive T cells?
CD8+ T Cells
Class II MHC is associated with which responsive T cells?
CD4+ T cells
Which cells express Class I MHC?
All nucleated cells
Which cells express Class II MHC?
Dendritic cells, phagocytes, B lymphocytes, endothelial cells, thymic epithelium
Src Tyrosine Kinases
c-Src, Lyn, Fyn, Lck
Syk Tyrosine Kinases
Syk, ZAP-70
Tec Family Kinases
Tec, Btk, Itk
SH2 domains
bind phosphotyrosine-containing polypeptides
SH3 domains
bind proline-rich stretches (hydrophobic areas)
PH domains
recognize PIP3 (or other phosphatidylinositol-derived lipids)
CD4 is associated with what type of T cells?
T helper
CD8 is associated with what type of T cells?
Cytotoxic T cells
Early Events in T Cell Activation
- Ag recognition - TCR complexes cluster with CD4 or CD8
- CD4-associated Lck becomes active, phosphorylates ITAMs of CD3 and zeta chains
- ZAP-70 binds phosphotyrosines of zeta chains that self-phosphorylate and are activated
- Active ZAP-70 activates (phosphorylates) adaptor proteins such as LAT
- Adaptors become docking sites for PLCγ11 and exchange factors that activate Ras and MAP kinases
PI3k
converts PIP2 to PIP3
Pro-B cells can eventually differentiate into:
follicular B cells, marginal zone B cells, and B-1 cells
Pro-T cells can commit to either:
αβ T cells or γδ T cells
Rag-1 and Rag-2
regulate BCR rearrangement - at the beginning of B cell life
Notch-1 and GATA-3
transcription factors that commit lymphocytes to T cell lineage
H-chain chromosome #
14
κ-chain chromosome #
2
λ-chain chromosome #
22
Order of BCR Diversity gene rearrangement
- D segment chosen (DJ)
- V segment chosen (VDJ)
- J chosen (VDJC)
Which segments in BCR and TCR do NOT have D segment?
BCR - light chain
TCR - α chain
What nucleotide sequence does RAG add?
p (palindromic)
What nucleotide sequence does TdT add?
n (nontemplated)
Which is the first polypeptide chain completed in B cells?
H
Which is the first polypeptide chain completed in T cells?
β
What are the three signals required for proliferation of T lymphocytes?
- Ag recognition
- Costimulation
- Cytokines
What are the steps in T-Cell Receptor Signaling?
- LCK is activated, phosphorlyation of CD3 and activation of ZAP70
- Activated ZAP70 phosphorylates LAT and SLP76
- LAT recruits GRB2, GADS, and PLC1
- PLC1 results in production of IP3 and DAG
- IP3 increases cytosolic free Ca2+
- DAG activates PKC
- LAT activates Ras and MAPK
CTLA-4
Mediates immune checkpoint induced in naive T cells at time of their initial response to Ag - inhibitor
PD1
Checkpoint that regulates inflammatory responses in tissues
IL-2
survival signal for T cells - increases expression of anti-apoptotic protein Bcl-2
CD69
Reduces surface expression of S1PR1 (keeps T cells in lymph node)
S1PR1
T cells will leave the lymph node
When is CD40 (CD154) increased in activated T cells?
24-48 hours after Ag recognition
When is CTLA-4 (CD152) increased in T cells?
24-48 hours after Ag recognition
T-bet
differentiation of effector cells in CD4+ T cells
Blimp-1
generation of memory cells
What are the two pathways from which memory T cells may develop?
- linear - some effector T cells “stick around” and become memory cells
- divergent - some cells will become memory cells “right away”
PLCγ - effect
catalyzes hydrolysis of PIP2 to IP3 and DAG
IP3
stimulates increase in cytosolic Ca2+ (from ER)
DAG
activates protein kinase C (PKC)
Ras*GTP pathway
activates ERK –> phosphorylates ELK –> transcribes fos –> combines with Jun and activates AP-1
Rac*GTP pathways
activate JNK –> phosphorylates Jun –> combines with fos and activates AP-1
Five NF-KB proteins
p65/RelA Rel B c-Rel p50/NF-KB1 (no activation domain) p52/NF-KB2 (no activation domain)
Canonical NF-KB pathway
- p65/cRel + p50 is bound to IKB (NF-KB inhibitor)
- activated IKK (IKB kinase) phosphorylates IKB protein and induces polyubiquiniation
- protease recognizes IKB-UUUUUUU signal and degrades
- NF-KB (the p65/cRel & p50) are released, translocated to nucleus, and activated
Alternative NF-KB pathway
- IKKα activated
- Phosphorylates RelB/p100 - partial proteolysis of P100 –> p52 (NF-KB2)
- NF-KB2/p52 dimerizes with RelB and translocates to nucleus
T-Cell costimulators
CD28 and CD80/60
Coreceptors on T helper cells
CD4
Coreceptors on cytotoxic T cells
CD8
Coreceptors on B cells
CD21, CD32, CD 19
Difference between coreceptors and costimulators
Coreceptors: can bind to same Ag ligand complex recognized by Ag receptor
Costimulators: “second signals” do NOT recognize ligands
Inhibitory receptors in T cells
CTLA-4
Inhibitor receptors in B cells
CD22 and FCγRIIB
TCR complex structure
αβTCR noncovalently linked to CD3 and ζ proteins (signal transducing subunits)
Positive co-receptors on B cells
CR2 (CD21) complex w/ CD19, CD81 - lower threshold for B cell activation and increase signaling response
Negative co-receptors on B cells
CD32 - contains ITIM, negatively regulates BCR signaling
What is the role of complement in B cell activation?
Complex of the CR2 complement receptor - CD19 and CD81 (TAPA-1)
Ag bound to complement fragment C3d can engage both CR2 and membrane Ig, leading to signaling cascades form both BCR and CR2 complexes
How does CR2 complex enhance response of BCR?
Binding of C3d-CR2 brings CD19 closer to BCR-associated kinases
This phosphorylates CD19 cytoplasmic tail
- Enhances phosphorylation of ITAM in Igα and Igβ
- Activates PI3-kinase
PI3 kinase activates Btk and PLCγ
FcγRIIB
inhibits activated B cells, DCs, and macrophages
CD22
inhibits B cells only
SHP
SH2-domain containing phosphatase (associates with ITIM of inhibitor receptors)
SHIP
SH2-domain containing inositol phosphatase (associates with ITIM of inhibitor receptors)
What are the two mechanisms of inhibitory signaling?
- Inhibitory receptors (recruit phosphatases)
2. E3 ubiquitin ligases
C3b and C4b activity and effect
Activity: opsonization of Ag
Effect: Increase phagocytosis by macrophages and neutrophils
C3a and C5a activity and effect
Activity: chemotaxis, degranulation
Effect: Attract neutrophils and monocytes to inflammatory sites, release of inflammatory mediators from mast cells and basophils
C3b activity and effect
Activity: clear immune complexes
Effect: reduce buildup of harmful Ab-Ag complexes
C3d activity and effect
Activity: B cell activation
Effect: Promote humoral immune response
Stages of lymphocyte maturation
stem cell –> pro lymphocyte –> pre lymphocyte –> immature lymphocyte –> mature lymphocyte
What cytokine stimulates development of T cell progenitors?
IL-7
What cytokine stimulates development of NK cells?
IL-15
Which transcription factors induce genes required for B cell development?
EBF, E2A, and PAX-5
What is the pre-BCR Ag receptor chain?
Ig μ heavy chain
What is the pre-TCR Ag receptor chain?
β chain
positive selection
process in which cells that have low avidity to self are stimulated to survive
* have low recognition of self-Ags, but can still recognize MHC
negative selection
T cells: if they have strong avidity to self-Ag, will be eliminated via apoptosis (clonal deletion)
B cells: get 2nd attempt in Ig rearrangement (receptor editing)
* κ to λ light chain
* if receptor editing fails, will have apoptosis
Pro B Cell options for proliferation and specialization
B1 cells
B2 cells - follicular B2 cells or marginal zone B2 cells
B1 cells
- derived from fetal-liver HSCs
- express limited BCR diversity b/c TdT is not expressed in fetal liver
- secrete IgM
B2 cells
- develop from bone marrow HSCs
* follicular B2 cells or marginal zone B2 cells
Follicular B2 cells
- require constant replenishment from bone marrow
- respond to Ag via T-cell dependent manner
- undergo Ig isotype switching
- after T-cell dependent activation, will develop to plasma cells and memory B cells
Marginal zone B2 cells
- localize to splenic marginal zone, respond to bloodborne Ag
- self-renewing
- respond independent of T cells
- limited BCR diversity
- respond to blood borne microbes and differentiate into short-lived IgM secreting plasma cells
αβ vs γδ T cells
10% T cells = γδ - have limited diversity
90% T cells = αβ