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ICB > Cytokines > Flashcards

Cytokines Flashcards

1
Q

Cytokine Families

A
  • different structural families
  • small proteins (15-25 kDa)
  • act locally in immediate environment (short range hormones)
  • exception of IL1 that has long range inflammatory effects/upregulating adhesion to epithelium
  • released by several different cell types and bind to specific cellular receptors
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2
Q

Cytokine Action

A
  • autocrine: self action
  • paracrine: local on nearby cells
  • endocrine (IL1): act via circulation on distant cells
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3
Q

Pleiotropic effects

A
  • 1 gene influences more than 1 phenotypic trait
  • 1 cytokine can have more than 1 effect on a cell
  • 1 cytokine can also act on different cells with the same effect
    eg. activated helper T cells secrete IL4 that target B cells, mast cells, and thymocytes with different effects
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4
Q

Cytokines Methods

A
  • redundant: many cytokines have same effect
  • synergistic: action of many produces more than their sum
  • antagonistic: 1 cytokine inhibits the action of another
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5
Q

Cytokine Families

A
  • 5 families
    1. Haematopoietins
    2. IL-1: inflammatory signals
    3. interferons: IFNa/b/y
    4. TNFs: TNFa/b
    5. Chemokines
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6
Q

Haematopoietic Cytokines

A
  • support growth and differentiation of haematopoietic cells
  • specific cytokines act on specific target
  • expression driven by specific TF
  • promotes differentiation to different blood cells
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7
Q

Interleukin 2

A
  • needed for expansion of activated T cells
  • IL-2 is the major cytokine/growth factor needed for T cell proliferation
  • made by activated T cells
  • signalling via CD3 complex and co-stimulatory signal activates NFAT (nuclear factor of active T cells) leading to IL-2 transcription
  • mRNA inherently unstable allowing precise temporal regulation of expression
  • co-stimulation stabilises IL-2 mRNA: IL-2 synthesis increases
  • creates a prolonged stable effect
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8
Q

Proliferation and differentiation of activated T cells

A
  • driven by IL-2
  • activation of T cells induces IL-2 synthesis and high affinity IL-2 receptor
  • binding of IL-2 to high affinity receptor triggers cell division
  • T cells divide 2-3x per day to generate huge numbers of effector cells with same antigen specificity
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9
Q

Steps of T cell Activation / Proliferation

A
  1. naive CD8 T cell activation caused by antigen recognition and MHC class 1 receptor
  2. IL-2 antibody secreted and recognised by IL-2 receptor to promote T cell differentiation
  3. Effector T cell recognise and kill virus infected epithelial target cells
    - native T cell have moderate affinity receptor
    - activated T cell has a high affinity receptor with a alpha chain
    - binding of IL-2 to the high affinity receptor sends a signal to the T cell inducing proliferation
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10
Q

T Follicular Helper Cells

A
  • produces cytokines needed for expansion of antigen activated B cells in lymph nodes
  • Helper Tfh cell conjugates with the B cell and begins to synthesize cytokines and CD40 ligand
  • CD40 is a TM protein in B cells that is a costimulatory signal
  • Helper Tfh cell reorients its cytoskeleton and secretory apparatus toward the B cell
  • Cytokines are secreted into the narrow space between the Tfh cell and the B cell
  • drives B cell proliferation
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11
Q

Ig Class Switching

A
  • cytokines from Th cells regulate B cell Ig class switching
  • cytokine production at site dictates type of immune response
  • what dictates type of cytokine : innate system recognises pathogen patterns leading to a type of cytokine produced
  • Isotype switching takes place in active B cells in the lymph node germinal center
  • cytokines induce, augment, or inhibit class switching to particular isotype
    (inhibition due to positive effect of cytokine in switching to another isotype)
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12
Q

Cytokine Receptors

A
  • 5 structurally distinct families
    1. homodimeric receptors
    2. heterodimeric receptors with common chain
    3. heterodimeric receptors without common chain
    4. TNF receptor family
    5. chemokine receptor family (GPCR)
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13
Q

Class 1 cytokine receptors

A
  • form subfamilies with common signalling subunits
  • eg. IL-2 receptor subfamily shares a common y subunit
  • sharing a signal subunit explains the redundancy of action and antagonism between cytokines in a subfamily
  • one chain determines specificty and one transmits the signal
  • same effect
  • different cytokines can then generate the same signal or compete for the signalling chains causing antagonism
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14
Q

JAK / STAT Signaling

A
  • general model of signal transduction mediated by most class 1 and class 2 (interferon) cytokine receptors
  • cytokine drives receptor complex formation
  • Janus Kinases dimerise and become activated
  • phosphorylation of STATs
  • STAT dimerisation, enter nucleus, and induce gene transcription
  • cytokine signalling is quickly regulated by dephosphorylation
  • SOCS proteins also bind to phosphotyrosine residues and target proteins for degradation
  • different combinations of JAK/STAT signal transducers link to different cytokine receptors
  • each STAT recognises a distinctive phosphotyrosine sequence on the receptor
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15
Q

CD4+ T cell Classes

A
  • different functional classes result from activation and development in different cytokine environments
  • Th1 cells: IL-12/IFN-y cytokines induce differentiation into this type, defining TF is T-bet, produces IL-12 and IFN-y, function of the TH1 cells is activation of macrophages
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16
Q

Different Types of T cells (helper)

A
  1. TH1: activates macrophages/enhances cytotoxicity
  2. TH17: enhance neutrophil response
  3. TH2: activate cellular and Ab response to parasites
  4. Tfh: activate B cells, maturation of Ab response
  5. T regulatory cells: suppresses other effector T cells
    - each differentiates using specific cytokines/TF
    - each secretes specific cytokines
17
Q

Pathogenic Cytokines

A
  • affect CD4 T cell differentiation
  • some pathogens induce IL-12 secretion by dendritic cells activating NK cells to produce IFN-y (PAMPs cause cytokine production)
  • naive T cells activate via IFN-y/IL-12 are committed to differentiate into TH1 cells
18
Q

Alarmins

A
  • parasites evolved ways to switch off immune responses
  • alarmin cytokines IL-25 and IL-33
  • specialised epithelial cells sensing parasitic molecules to produce cytokines dealing with parasites
  • IL33 also made by epithelial cells from damage caused by parasite migration
  • alarmin response promotes TH2 cell proliferation
19
Q

TH1 Cytokines

A
  • IFNy activates macrophages, induces B cell class switch to IgG3 (good at opsonization)
  • TNFa activates macrophages and NK cells
  • IL-2 stimulates CTLs and NK cell proliferation
  • best for intracellular pathogens
20
Q

TH2 Cytokines

A
  • IL-4 induces B cell proliferation and class switch to IgE
  • smooth muscle contraction and fluid secretion
  • IL-5 augments production of IgA by B cells
  • IL-13 promotes IgE class switch, induces goblet cell proliferation and mucus production
  • optimal for pathogens like parasites or mucosal infection (class switching to Abs best for this)
21
Q

TH1/TH2 production

A
  • signalling through TCR and cytokine receptors determines production of TH1 and TH2 promoting transcription factors
  • initial cytokine environment important in driving differentiation
  • T-bet commits T cells to TH1 pathway
  • GATA-3 commits T cells to differentiate along TH@ pathway
  • each pathway shuts down the other
22
Q

Cytotoxicity

A
  • lymphoid cells (T and NK) recognise infection and induce apoptosis
  • produce pore forming proteins to punch holes
  • granzymes enter cell and initiate capase cascade
  • myeloid cells (neutrophils/macrophages) are indiscriminate
  • ingest pathogens or cells and cause an oxidative burst making ROS and cyto-toxic species
23
Q

Cytokine Production of CD4+ and CD8+

A
  • different classes of CD4/8 T cells have distinctive cytokine production profiles
  • each cytokine production leads to different functions of the T cell (helper, inflammation, cytotoxic effects)

ICB (15 decks)

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