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IBI Test 4 > B3.059 Cell Signaling in the Immune System > Flashcards

B3.059 Cell Signaling in the Immune System Flashcards

1
Q

what are the 3 steps in signal transduction

A
  1. signal perception upon ligand binding
  2. intracellular signal transduction
  3. cellular response
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2
Q

common themes in signal transduction

A

conformational change of proteins
post-translational modification of proteins
protein movement within a cell (translocation)
protein-protein interactions
second messengers
altered gene transcription
pathway downregulation

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3
Q

3 major classes of kinases

A

receptor tyrosine kinases
non-receptor tyrosine kinases (JAK)
MAPK

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4
Q

what is the primary function of kinases/phosphatases

A

molecular switches for turning cells on and off again

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5
Q

how does phosphorylation occur

A

each phosphate group carries 2 negative charges

major conformational change in the protein by attracting a cluster of positively charged amino acid side chains

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6
Q

what is the affect of the conformational change induced by phosphorylation

A
  1. affects the binding of ligands elsewhere on the protein surface, changing the proteins activity
  2. attached phosphate group can form part of a structure that the binding sites of other proteins recognize (SH2, SH3)
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7
Q

what receptor exhibits kinase activity

A

growth factor receptors

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8
Q

what receptors are associated (non covalently) with kinases

A

associated all the time
-cytokine receptors
associate with receptor after ligand binding
-antigen receptors (BCR, TCR)

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9
Q

how do receptors with intrinsic or associated kinase domains work

A

ligand binding dimerizes the receptor, activating the kinases which phosphorylate each other
activated kinases phosphorylate downstream substrates

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10
Q

discuss the physical structure of JAKs

A

Janus Kinase
-has 2 near identical phosphate transferring domains, one w kinase activity and one that negatively regulates the kinase activity
proline rich region of membrane proximal receptor (Box 1/ box 2 domain)

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11
Q

what are the JAKs

A

JAK1-4, TYK2

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12
Q

what are STATs

A

signal transducers and activators of transcription

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13
Q

classify STATs

A

7 members in mammals

STAT 1-4, 5a and b, 6

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14
Q

discuss the binding properties of STATs

A 
phosphorylated by JAK, RTK, c-src
bind GAS (gamma activated sites) or ISREs
homo/heterodimerize via SH2 domains post phosphorylation
coiled-coil domain = nuclear localization signal
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15
Q

which cytokines utilize JAK1 and JAK3

A

IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R

have shared gamma subunit

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16
Q

cytokines that activate STAT1

A

type 1 IFNs and IFN-y

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17
Q

cytokines that activate STAT2

A

type 1 IFNs

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18
Q

cytokines that activate STAT3

A

may

esp gp130 cytokines

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19
Q

cytokines that activate STAT4

A

IL-12

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20
Q

cytokines that activate STAT5a and b

A

IL-2

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21
Q

cytokines that activate STAT6

A

IL-4

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22
Q

depict the general model of signal transduction mediated by most class 1 and 2 cytokine receptors

A
  1. binding of cytokine causes dimerization of receptors and activation of JAK kinases
  2. activated JAK kinases phosphorylate receptor sites and create docking sites for STAT molecules
  3. phosphorylation of STAT by JAK kinase
  4. the phosphorylated STATs dimerize and translocate to the nucleus where they activate transcription of specific genes
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23
Q

proteins involved in type 1 interferon signaling

A

IFNa, B
JAK1, TYK2
STAT1-STAT2
antiviral response

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24
Q

proteins involved in type 2 interferon signaling

A

IFNy
JAK1, JAK2
STAT1- STAT1

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25
Q

what are the components of the IL2 high affinity receptor

A

IL2Ra, IL2RB

gamma common chain (CD132)

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26
Q

proteins involved in IL2 signaling

A

JAK1, JAK3 ( JAK3 always bound to gamma c chain)
STAT5a and b
Ras
PIP2/IP3/DAG

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27
Q

describe JAK3 X-linked SCID

A

JAK3 is essential for cytokine signaling mediated by gamma c cytokines
mutations lead to inactivation of signaling pathways
no T or NK cells, but normal B cell numbers
cytokines are required for development of T and NK cell types

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28
Q

what does kinase driven phosphorylation provide

A

docking sites for SH2 domain-containing receptors and platforms on which signaling cascades are established

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29
Q

how is the JAK/STAT pathway negatively regulated?

A

phosphatases/molecules which prevent phosphorylation

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30
Q

what are the primary classes of phosphatases/molecules which prevent phosphorylation

A 
SHP1, SHP2 (SH2 domain)
SHIP (SH2 domain)
CD45
SOCS
PIAS
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31
Q

non receptor protein tyrosine phosphatases

A

SHP1, SHP2

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32
Q

inositol phosphatase

A

SHIP

33
Q

receptor tyrosine phosphatase

A

CD45

34
Q

prevent further phosphorylation

A

SOCS

PIAS

35
Q

remove phosphates directly

A

SHP1, SHP2
SHIP
CD45

36
Q

how does PIAS work

A

protein inhibitors of activated STAT
inhibit STAT1 and STAT3
binding and blocking access to GAS

37
Q

what is a SOCS

A

suppressors of cytokine signaling

38
Q

what are the 3 primary domain structures of SOCS1 and SOCS3

A

KIR
classical SH2
SOCS box

39
Q

what does the KIR do

A

inhibit JAK kinase activity directly
binds activation loop of JAK catalytic domain
functions as a psuedosubstrate

40
Q

what does the SH2 domain do

A

for binding to phosphorylated receptor and/or phosphorylated JAKs (docking)

41
Q

what does the SOCS box do

A

target entire cytokine receptor complex, including JAKS and SOCS themselves for ubiquitin mediated proteasomal degradation

42
Q

how can the SOCS family shape macrophage polarity

A

high SOCS1 to SOCS3 ratio associated with M2 macrophage polarization
high SOCS3 associate with M1 macrophage polarization
based on selective inhibition of signaling pathways

43
Q

Ruxolitinib

A

inhibits JAK1, JAK2
reduces spleen size (site of extramedullary hematopoiesis)
treats myelofibrosis

44
Q

Tofacitinib

A

inhibits JAK3
interferes with IL2 and IL4 signaling
approved for treatment of rheumatoid arthritis

45
Q

what are the innate immune sensors

A

TLRs, RIGI like receptors, NOD like receptors

46
Q

what are the most important innate immune sensors

A

TLRs

on macrophages, dendritic cells, and others

47
Q

what do TLRs detect

A 
wide range of ligands
bacterial, viral, fungal
ECM fragments
nucleic acids
intracellular proteins
48
Q

what 2 intracellular signaling pathways does TLR4 utilize

A

Myd88-dependent (fast, 2-5 min)
Myd88-independent (TRIF-dependent) (slow, hour)
both activate NF-kB

49
Q

what is required for NF-kB mediated gene transcription

A

phosphorylation of IkB by IKK complex to liberate NFkB

only then can NFkB translocate to the nucleus to regulate gene transcription

50
Q

what does TLR4 recognize

A

LPS

51
Q

CD4+ T cell effector functions

A
  1. CD4+ binds MHC class 2
  2. both CD4+ cell and APC release cytokines
  3. cytokines cause T cell to cone itself
  4. clonal T cells produce different cytokines to activate B cells and CD8+ T cells
52
Q

CD8+ T cell effector functions

A
  1. CD8+ cell binds MHC class 1 and produces granzymes and perforins
  2. perforins form pores in plasma membrane, granzymes enter the cell and break down proteins, lysing the cell
53
Q

describe the process of proximal T cell signaling

A
  1. TCR sees Ag in the context of MHC
  2. CD4/CD8 is associated with Lck
  3. binding causes dissociation of CD45 p-tase
  4. Lck activated and phosphorylates 10 ITAMs in CD3 chains
  5. Zap70 docks to phosphorylated CD3 zeta chain
  6. Lck phosphorylates Zap70 (active)
  7. Zap70 autophosphorylates
  8. Zap70 phosphorylates many linker/adaptor proteins of the distal T cell activation pathway
54
Q

what are the 2 primary proteins involved in distal T cell signaling

A

LAT and SLP-76
phosphorylated by zap70
initiate 4 downstream pathways

55
Q

what are the 4 downstream signaling modules of distal T cell signaling

A
  1. Akt-mediated increase in metabolic activity
  2. PLCy-mediated increases in calcium and IL2 production
  3. Vav activation and cytoskeletal reorganization
  4. ADAP recruitment integrin activation/clustering to improve adhesion
56
Q

why is IL2 so important for T cells

A

promotes cell growth
promotes cell survival
promotes differentiation into effector cells
promotes differentiation into memory cells
required for T reg development

57
Q

2 important signaling molecules generated by PLC-y

A

PIP3

DAG

58
Q

what does PIP3 do

A

opens calcium channels to allow Ca2+ release from the ER into cytosol
leads to STIM1 aggregation
STIM1 aggregation opens a channel allowing entry of extracellular calcium

59
Q

what does DAG do

A

activates PCK which is required for NFkB activation

60
Q

what is NF-AT

A

transcription factor regulated by calcium signaling

61
Q

discuss the regulation of NF-AT

A
  1. phosphorylation on serine and threonine residues keeps NFAT in the cytoplasm of unstimulated cells
  2. calcium entry activates the serine/threonine phosphatase calcineurin which dephosphorylates NFAT
  3. dephosphorylated NFAT enters the nucleus and activates gene transcription (IL2)
62
Q

calcineurin inhibitors

A

cyclosporine, tacrolimus
promote graft survival after liver transplant
prevents dephosphorylation of NFAT
suppress IL2 transcription

63
Q

mechanism of cyclosporine (CsA)

A
  1. CsA binds cyclophilin (CpN)
  2. complex bind and blocks function of calcineurin
  3. downstream signaling cannot produce IL2
    full T cell activation prevented
64
Q

mechanism of tacrolimus (FK506)

A
  1. FK506 binds FK506-binding protein (FKBP)
  2. binds and blocks CaN
  3. downstream signaling cannot produce IL2
    full T cell activation prevented
65
Q

what co stimulatory molecules provide signals for T cell activation

A

CD28: B7-1/2
CD40: CD40L
ICOS:ICOSL

66
Q

what co stimulatory molecules provide signals for T cell down regulation

A

CTLA4: B7-1/2
PD-1:PD-L1/2
BTLA:HVEM

67
Q

how does CTLA4 work

A

outcompetes CD28 for binding

68
Q

ipilimumab

A 
targets CTLA4 (cytotoxic T lymphocyte associated protein 4)
melanoma
NSCLC, SCLC, bladder cancer metastatic, hormone refractory prostate cancer
69
Q

pembrolizumab

A

targets PD-1 (programmed cell death)
any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsattelite instability high state

70
Q

suppressing the immune system with Treg cells

A

maintain self tolerance
suppressing self reactive lymphocytes that recognize Ag different from those recognized by the conventional T cells
intermediate affinity for self MHC: peptide complexes

71
Q

proteins expressed by Treg cells

A

CD4+, Foxp3+, CTLA4 high, TGFB, IL10, IL35

72
Q

why do Treg cells require IL2

A

development and for suppressive activity

73
Q

mutations in Treg cells can cause what

A

IPEX (immune dysregulation, polyimmune endocrinpathy, enteropathy, X-linked)

74
Q

describe T cell anergy

A

signal 1 without signal 2
an inactive state
mechanism of immunological tolerance
cancers often downregulate molecules that provide signal 2

75
Q

what is the outcome of B cell activation

A 
Ig class switching
terminal differentiation into Ab-secreting plasma cells
production of memory B cells
with or without T cell help as defined in the next slides
76
Q

describe T cell independent B cell activation

A

TLR/PAMP/DAMP interaction

activation of B cell and secretion of pentameric IgM

77
Q

describe T cell dependent B cell activation

A

cytokines produces by CD4+ T cells stimulate clonal expansion and production of memory B and plasma cells

78
Q

describe the overarching steps in B cell signaling via the BCR

A
  1. cross linking of membrane Ig by antigen
  2. tyrosine phosphorylation events
  3. biochemical intermediates
  4. active enzymes
  5. transcription factors (NFAT, NF-kB, AP-1)

IBI Test 4 (21 decks)

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