Lectures 10 (linked to 12)

Cytokines and Immune Response

September 17 & 24, 2004

Chris Schindler
cws4@columbia.edu

Reading: Janeway - as indicated

Abbas - Chapter 11
 Blood: 4-10,000 WBC per 1 L

Lymphocytes - 10-15 % Granulocytes - 35-80 %

(T-, B- & NK cells) PMNs Eos Basos

35-80 % 0-8 % 0-2 %

How did they get there?

Monocytes - 0-15 % Where are they going?
What regulates them?

Think Cytokines, Growth

Factors & Chemokines!!!!
(Macs & DCs)
 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-, 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

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 Fibroblast IFN Leukocyte IFNs

• a.k.a IFN- • a.k.a IFN- • a.k.a IFN-’s
• critical for adaptive Immune • very potent • most prevalent
• made by T-cells & NK cells • made by all cells • made by all cells
• only one member • only one member • > 10 members

Type II IFN Type I IFN

 Type II IFN Signaling Paradigm

STAT1
P
P
P

STAT1
P
P

inflammation*
macrophage act.*
chemokines*
IRF1 (antiviral transcription factor)
P
MIG (a chemokine)
P GBP (anti-viral protein)
iNOS (nitric oxide synthase)
CIITA (transcription factor that
Gamma-activated sequence 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 production (from
Macrophages) during Septic Shock
Serum Cytokine Level

TNF- IL-1 IL-12

o 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-
and their
corresponding
receptors, are
in two different
families and IL-4 TNF- Trimer
have two
distinct types
of structures.

TNF Monmer/
Fig. 2-38 IL4/IL4 Receptor Receptor Monomer
Top half of Fig. 2-47
 V. Cytokines you need to know
Innate Adaptive
IL-2 (big family e.g. IL-7 & IL-15) √√
Type I & II IL-4 (small family inc. IL-13) √√
IL-6 (large family inc. G-CSF) √√ √
Cytokine
IL-10 (growing family) √√ √√
Receptors IL-12 (small family inc. IL-23) √√ √
(Hematopoietin R.) IFN- √√ √√
IFN- (large family) √√
Toll (TLR) /IL-1 IL-1 √√
Receptors IL-18 √√ √

LT- √ √√
TNF Related TNF- √√
Receptors CD40L √ √√
FasL √√ √√
TGF-
Receptors TGF- (very large family) √√ √√

Chemokine Chemokines (see Fig. 11.6)

Receptors Inflammatory √√ √√
Non-inflammatory √√ √√

See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas