ch. 3 - cytokines + chemokines

cytokine signaling

• inducing stimulus

PAMPs

antigen

DAMPs

cytokines

cytokine signaling

• induced response

enzyme activation

transcription

metabolism

chemotaxis

cytokine signaling

• effector response

proliferation

degranulation

phagocytosis

cytokine secretion

autocrine cytokine signaling

autoimmune cell expresses receptor for a self-made cytokine

paracrine cytokine signaling

immune cells secrete cytokines into environment and nearby cell expresses receptor

endocrine cytokine signaling

immune cells secrete cytokines into environment and travel long distances to receptor

pleiotropy

single cytokine produces multiple, distinct effector responses

synergy

2 (or more) cytokines produce effect together that neither produce alone

redundancy

2 (or more) cytokines produce an identical effect even in combination

antagonism

1 cytokine blocks or prevents the effector reponse produced by another

cytokine molecular signaling pathway

1. cytokine receptor waits w/ receptor -associated kinase

2. cytokine binds + receptor chains dimerize + become phosphorylated

3. transcription factors bind to phosphorylated chains

4. dissociate + turn into active transcription factors that bind to promoter

class 1 (hematopoietins, IL-2) cytokines utilize ________ signaling

JAK/STAT

class 1 cytokines effector outcomes

survivial

proliferation

differentiation

class 1 cytokine receptor subunit formation

1. intermediate affinity IL2R: beta + gamma subunits

2. TCR activation → alpha subunit binds to beta + gamma

3. high affinity IL2R

JAK/STAT negative feedback loop

1. IL6 binds to IL6R

2. proceeds as normal

3. 2 products: SOCS and proinflammatory effector molecules

SOCS

self-made product that inhibits JAK/STAT signaling

interferons (class 2 cytokines) are potently _________

antiviral

type 1 interferons

cytokines: IFN-alpha, IFN-beta, others

expression: ubiquitous

type 2 interferons

cytokines: IFN-gamma

expression: T cells

type 3 interferons

cytokines: IFN-lamda

expression: barrier tisssues

IFNAR 1/2

activated by IFN-alpha and beta

IFNLR1/IL10R2

activated by IFN-lamda

IFNGR1/2

activated by IFN-gamma

• forms ONLY STAT1/1 heterodimer

interferon stimulated response element

binds to STAT 1-2 heterodimer

• comes from type 1 and type 3 interferons

• functional transcription complex → interferon-stimulated genes (ISGs)

gamma interferon activation

binds to STAT 1/1 homodimer

• comes from all interferons

• functional transcription complex → interferon-stimulated genes (ISGs)

type 1 IFN positive feedback regulation steps

1. PAMP binds to PRR

2. 2 TBK1s phosphorylate 1 IRF3s → IRF3 homodimer → IFNBeta promoter

3. IFN-beta activate → IFNAR1/2 → STAT1-2 heterodimer → IRF7 promoter

4. IRF7 activated → induces IFNAlpha promoter → IFN-Alpha active

5. reactivates IFNAR1/2!

types of ISG effector molecules

• IFITM proteins

• OAS/RNAse L

• Protein Kinase R (PKR)

• Mx proteins

IFITM proteins

bloackade of viral entry/ endocytosis

OAS/RNAse L

RNA degradation/ editing

Protein Kinase R (PKR)

inhibition of translation

Mx proteins

inhibition of viral assembly

chemokines

cytokines that coordinate cellular movement

chemotaxis

chemical induced cellular movement

• attracted to source of chemokines

4 subfamilies of chemokines

1. CC

2. CXC

3. CX₃C

4. XC

how are the ligands and receptors of the families named?

add L and R to the end of the names

chemokines exhibit _________ receptor binding

promiscuous

• many ligands bind to receptors

CXCR1 ligands

L6 and L8

CXCR2 ligands

L1-3, L5-8

CXCR3 ligands

L9-11

CXCR4

only L12 — NON-promiscuous!

chemokine pleiotropic functions (GCPR)

1. AKT supresses apoptosis

2. cytoskeletal reorganization

3. gene expression

CXCR7/ ACKR3

NOT GCPR! atypical chemokine

1. R7 binds to L12 → endocytosis of receptor-ligand complex

2. complex binds to lysosome → L12 degraded

3. R7 goes back to cell surface w/o L12

naive B cell chemokines

(B cells) CXCR5 → CXCL13 (made by follicular dendritic cells)

naive T cell chemokines

(T cells) CCR7 → CCL 19/21 (made by reticular fibroblasts)

what if B and T cells meet their Ag?

their receptors are downgraded and they leave through efferent pathways

locations of PRRs

extracellular (PM), cytosolic and endosomal

extracellular PRRs

TLR + CLR

cytosolic PRRs

cGAS, NLR and RLR

endosomal PRRs

TLR

gram positive bacteria TLRs (extracellular)

diacyl lipopeptides → TLR2 + TLR6

fungi TLRs (extracellular)

triacyl lipopeptides → TLR2 + TLR1

flagellated bacteria TLRs (extracellular)

flagellin → TLR5 homodimers

gram negative bacteria (extracellular)

LPS → TLR4 homodimers

TLR adaptor molecules

MyD88 and TRIF

what do the TLR adaptor molecules turn on?

NF-kB (inflammatory) and IRFs (type 1 IFNs)

NF-kB activation

1. TLR + IKK active

2. IKK phosphorylates IkB (inhibitor) → IkB degraded

3. NF-kB can bind to kB site → immune response

IRF activation

1. TLR + TBK1 active

2. TBK1 phosphorylates IRF3

3. IRF3 homodimer → induction interferon expression

CLRs detect ________ PAMPs and induce _______

carbohydrate, phagocytosis

CLR induced phagocytosis

1. yeast/fungus detected by dectin-1

2. Syk activates NF-kB

3. simultaneously, phagosomes take up yeast/ fungus

2 major RLRs

RIG-I and MDA-5

RIG-I activation

RIG-1 binds to ssRNA

MDA-5 activation

MDA-5 binds to dsRNA

RLR combined immune response

1. MAVS activates TBK1

2. TBK1 phosphorylates IRF3 → IRF3 homodimer

3. induces type 1 IFNs

cGAS/STING detect _______ DNA and induce ____

cytosolic, IFNs

cGAS immune response

1. cGAS detects cytosolic DNA

2. cGAMP activates STING (endoplasmic ret)

3. STING activates TBK1 → IRF3 phosphorylation → IRF3 homodimer

4. type IFNs1

nod-like receptors (NLRs) sense cytosolic insults + form _________

inflammasomes

NLRP3 activation

sterile insults: pore formation, ion flux, crystal and ROS

NLRC4 activation

bacterial flagellin

AIM2 activation

cytosolic dsDNA

NLR inflammasome functions

process IK-1 cytokines = inflammation

procces GSDM-D = pyroptosis