Transcript What are cytokines and chemokines?

Lectures 10 (linked to 12)
Cytokines and Immune Response
September 17 & 24, 2004
Chris Schindler
[email protected]
Reading: Janeway - as indicated
Abbas - Chapter 11
Blood: 4-10,000 WBC per 1 mL
Lymphocytes - 10-15 %
(T-, B- & NK cells)
Monocytes - 0-15 %
(Macs & DCs)
Granulocytes - 35-80 %
PMNs
35-80 %
Eos
0-8 %
Basos
0-2 %
How did they get there?
Where are they going?
What regulates them?
Think Cytokines, Growth
Factors & Chemokines!!!!
What are cytokines and
chemokines?
• Small (10-30 kDa) secreted peptides (usually
glycosylated).
• They bind to specific receptors on target cells
to elicit a specific biological response.
• Expression of cytokines and their receptors is
usually tightly regulated.
• Other more anachronistic terms include
monokines and lymphokines.
What do cytokines, chemokines
and growth factors do?
• They direct the development,
maturation, localization,
interactions, activation and life span
of immune cells.
• Thus they play an essential role in
regulating immunity (adaptive and
innate).
How many flavors regulate
immunity?
•
•
•
•
•
•
Growth Factors (e.g., CSF-1, SCF)
IL-1 Family (e.g., IL-1, IL-18 & “Toll-like”)
TNF Family (e.g., TNF-a, CD40L, FasL, LT-b)
TGF-b Family (e.g., TGF-b )
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, GMCSF, IFN-g, IFN-a/b)
• Also steroid hormones and prostaglandins
Other important facts about Cytokines,
Chemokines & Growth Factors
• There are functional similarities within ligand
families (see summary).
• There are important functional differences
between ligand familes (see summary).
• These functional characteristics are determined
by the class of receptors these ligands bind.
• These ligands function at three distinct ranges:
– Autocrine*
– Paracrine*
– Endocrine*
*Make sure you have an example of each
Additional important concepts
• Properties of cytokines and chemokines.
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.
• Innate vs. Adpative Immunity
Innate Immunity
Per-wired first line of defense (more primitive)
Recognizes ~103 pathogen derived molecules (analogous to antigens)
Most important during initial minutes and hours of infection
Macrophages, Granulocytes and NK cells
Adaptive Immunity
Second, but very potent line of defense
Antigen specific response - recognizes ~107 antigens
Constitutes immunological memory for specific antigens
T-cells and B-cells
Cytokines and the innate
response to a viral infection
• The innate response is often quite effective
• The subsequent adaptive immune response
is important for many viral pathogens and
very important for immunization strategies
Innate Viral Interfering Activity is
Discovered in Cultured Cells (1950s)
X
Fractionating Viral Interfering Activity Leads
to the Discovery of Interferons (IFNs)
Immune IFN
• a.k.a IFN-g
• critical for adaptive Immune
• made by T-cells & NK cells
• only one member
Type II IFN
Fibroblast IFN
Leukocyte IFNs
• a.k.a IFN-b
• very potent
• made by all cells
• only one member
Type I IFN
• a.k.a IFN-a’s
• most prevalent
• made by all cells
• > 10 members
Type II IFN Signaling Paradigm
STAT1
P
P
P
STAT1
P
P
P
P
Gamma-activated sequence
inflammation*
macrophage act.*
chemokines*
IRF1 (antiviral transcription factor)
MIG (a chemokine)
GBP (anti-viral protein)
iNOS (nitric oxide synthase)
CIITA (transcription factor that
induces MHC)
Figure 6-23
Figure 2-48
Figure 2-49
Identification of “High IFN Producing Cells”
(HIPCs) in vivo
A small
subset of
WBCs
produce
most of the
circulating
IFN-Is
Cytokines and the innate
response to a skin infection
Wound Infection: Innate  Adaptive
Figure 2-3
Figure 2-5 part 1 of 2
Figure 2-8 part 1 of 2
Figure 2-39
Figure 2-15
QuickTime™ and a
GIF decompressor
are needed to see this picture.
Cytokines and the response to
sepsis
• Injection of LPS (a molecular pattern
molecule found on G- bacteria) is a model
system for sepsis.
• The host response to sepsis is often
referred to as the Acute Phase Response
(APR).
Local vs.
systemic
infection
TLR-4 and
company enable
macrophages to
sense and
respond to LPS
(to be covered in
detail in a later
lecture)
Figure 2-39
Serum Cytokine Level
Serum cytokine production (from
Macrophages) during Septic Shock
TNF-a
o
IL-1
IL-12
1
3
6
Hours after LPS injection
Note, this is one of the few times you can meaningfully
measure serum cytokine levels!!
Figure 2-46
IL-4 & TNF-a,
and their
corresponding
receptors, are
in two different
families and
have two
distinct types
of structures.
Fig. 2-38
IL-4
IL4/IL4 Receptor
TNF-a Trimer
TNFa Monmer/
Receptor Monomer
Top half of Fig. 2-47
V. Cytokines you need to know
Innate
Adaptive
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IL-2 (big family e.g. IL-7 & IL-15)
IL-4 (small family inc. IL-13)
IL-6 (large family inc. G-CSF)
IL-10 (growing family)
IL-12 (small family inc. IL-23)
IFN-g
IFN-a (large family)
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IL-1
IL-18
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LT-a
TNF-a
CD40L
FasL
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TGF-b
Receptors
TGF-b (very large family)
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Chemokine
Receptors
Chemokines (see Fig. 11.6)
Inflammatory
Non-inflammatory
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Type I & II
Cytokine
Receptors
(Hematopoietin R.)
Toll (TLR) /IL-1
Receptors
TNF Related
Receptors
See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas
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