lectures 12 cytokines and immune response september 24, 2004 chris schindler [email protected]...
TRANSCRIPT
Lectures 12
Cytokines and Immune Cytokines and Immune ResponseResponse
September 24, 2004
Chris [email protected]
Reading: Janeway - as indicatedAbbas - Chapter 11
• Small proteins that bind to specific receptors on target cells.
• The expression of cytokines and their receptors is tightly regulated (temporally and geographically).
• They direct the development, maturation, localization, interactions, activation and life span of immune cells.
• These ligands function at three distinct ranges: autocrine, paracrine and endocrine.
Quick review of cytokines, chemokines & growth
factors
• Pleiotropism - activate numerous types of responses, e.g., differentiation, growth, activation and chemotaxis.
• Redundancy - i.e., functional overlap.• Synergy - between cytokines to maximize
a response. • Antagonism - to regulate duration and
potency of response. It is critical to maintain a delicate balance to avoid autoimmunity.
• Feedback and Feedforward Loops - for negative and positive (e.g., signal amplification) regulation.
Properties of cytokines and chemokines
Properties of Cytokines
Abbas: Chpt. 11; Fig. 11.2
• Growth Factors (direct hematopoiesis and endothelial cell growth/activity)
• IL-1 Family (e.g., IL-1 & “Toll-like”) • TNF Family (e.g., TNF-, CD40L, FasL) • TGF- Family (e.g., TGF- ) • Chemokines (e.g., CC and CXC families)• Hematopoietins / a.k.a. Four Helix Bundle (e.g.,
IL-2, IL-4, IL-6, IL-10, IL-12, IFN-, IFN-/)
Cytokines, chemokines and growth factors can be placed into several structurally & functionally related
families
For adaptive CD8 immunity
An innate response
Figure 2-39
Biological actions of TNF
Abbas: Chpt. 11
NewAnti-inflammatory Agents
Remicade (infliximab)Anti-TNF
Enbrel (etanercept)TNF-Trap
Kineret (anakinra)rIL1-RA
• Naïve CD4+ T-helper cells are activated into different types of effector T-cells.
• We will focus on the development of Th1 and Th2 effector cells
Cytokines and the Th1-Th2 paradigm
Figure 8-24
Figure 8-10
IL-2
Figure 8-24
Most of Fig. 8-27
Most of Fig. 8-31
Important Th1 effector cytokines
Figure 8-19
The IL-2 autocrine
loop
Stimulation of the low
affinity IL-2 receptor leads to
induction of IL-2 and IL-2R -chain to generate high affinity
receptor, culminating in potent
T-cell proliferation
.
Let’s digress to review TCR
signaling for an
important clinical pearl!
TCR-mediated Signal Transduction:
A Tyrosine Kinase Cascade
Abbas & Lichtman, Fig. 8-7, p. 175
NF-AT and TCR-mediated
Signal Transduction
Abbas & Lichtman, Fig. 8-12, p. 183 (see Fig. 14.5 in Janeway, p618)
Cyclosporin A (CyA) & Tacrolimus (FK506) are two important drugs that block calcineurin activation NF-AT activation IL-2 production! They are therefore potent immunosuppressive drugs.
IFN- is considered the Th1 signature cytokine.
IL-4, IL-5 and IL-6 are Th2 cytokines and promote
humoral immunity
IL-10 and TGF-IL-10 and TGF- are also are also Th2 important effector Th2 important effector cytokines that potently cytokines that potently antagonize cellular antagonize cellular immunity. immunity.
QuickTime™ and aGIF decompressor
are needed to see this picture.
IL-4IL-4 is the signatureis the signatureTh2 effector cytokineTh2 effector cytokine
Figure 9-6
Figure 9-7
Polarization of CD4+ T-cells into functional Th1 and Th2
subsets
Th0
IL-5
IL-4
IL-6
Th1 Th2
IL-2
IFN-
IL-12 IL-4
TNF
““The Allergic Limb”The Allergic Limb”““The Allergic Limb”The Allergic Limb”““The Autoimmune Limb”The Autoimmune Limb”““The Autoimmune Limb”The Autoimmune Limb”
NaïveCD4+
T-helper
DC
- Defense against - Defense against parasitesparasites- Ab production & class - Ab production & class switch switch
AllergyAllergyGraft-vs-host diseaseGraft-vs-host disease
Rheumatoid arthritisRheumatoid arthritisType I Diabetes mellitusType I Diabetes mellitus
Multiple sclerosisMultiple sclerosis
Pathophysiology of the Pathophysiology of the balance between Th1 and balance between Th1 and
Th2Th2
Th1 Th2
- Defense against virus & - Defense against virus & intra- intra- cellular cellular pathogenspathogens- Anti-tumor immunity DTH - Anti-tumor immunity DTH
Figure 8-32
Chemokines
Chemokines signal Chemokines signal through G protein- through G protein- coupled receptors coupled receptors making them making them desirable drug desirable drug targetstargets
QuickTime™ and aGIF decompressor
are needed to see this picture.
Leukocytes Leukocytes express unique express unique sets of sets of chemokines chemokines receptors receptors allowing them allowing them to be targeted to be targeted to the to the appropriate appropriate tissuestissues
**CCL2
CCL5
CX3C
**CXCL8
CXCL3
CXCL8**CXCL7
FYI - some of the chemokine leukocyte specific activities
Non-inflammatory (i.e., development/homing vs. inflammatory chemokines
CCL3**CXCL1,2,3 CXCL1,2,3
CXCL10CXCL10 CXCL10 (th1)
CXCL12 CCL3CCL3 (th1)
CCL4CCL4
CCL4
CCL2CCL2 (th2)
CCL5**CCL5
**CCL18XCL1
XCL1
** Activating chemokine
Chemokines are Chemokines are much more than much more than
just just chemoattractantschemoattractants
QuickTime™ and aGIF decompressor
are needed to see this picture.
CXCL12
CXCR4
Chemokine Redundancy
Abbas: Chpt. 11
Figure 2-41
Of Note . . . . .
•Two chemokine receptors serve as co-Two chemokine receptors serve as co-receptors for HIV infection (CXCR4 and receptors for HIV infection (CXCR4 and CCR5)CCR5)
• Growth Factors (e.g., CSF-1, SCF) • IL-1 Family (e.g., IL-1, IL-18 & “Toll-like”) • TNF Family (e.g., TNF-, CD40L, FasL, LT-) • TGF- Family (e.g., TGF- ) • Chemokines (e.g., CC and CXC families)• Hematopoietins / a.k.a. Four Helix Bundle (e.g.,
IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, GM-CSF, IFN-, IFN-/)
• Also steroid hormones and prostaglandins
How many flavors regulate immunity?
Cytokine Receptor Classes
Abbas: Chpt. 11