Lectures 10 (linked to 12)Cytokines and Immune Cytokines and Immune

ResponseResponse

September 17 & 24, 2004

Chris Schindlercws4@columbia.edu

Reading: Janeway - as indicatedAbbas - Chapter 11

Blood: 4-10,000 WBC per 1 L

How did they get there?Where are they going?What regulates them?

Think Cytokines, Growth Factors & Chemokines!!!!

Lymphocytes - 10-15 %

(T-, B- & NK cells)

Monocytes - 0-15 %

(Macs & DCs)

Granulocytes - 35-80 %

PMNs35-80 %

Eos0-8 %

Basos0-2 %

• 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 are cytokines and chemokines?

• 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).

What do cytokines, chemokines and growth

factors do?

• 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?

• 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

Other important facts about Cytokines, Chemokines & Growth

Factors

• 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 ImmunityInnate 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 infectionMacrophages, Granulocytes and NK cells

Adaptive ImmunitySecond, but very potent line of defenseAntigen specific response - recognizes ~107 antigensConstitutes immunological memory for specific antigensT-cells and B-cells

Additional important concepts

• The innate response is often quite effective

• The subsequent adaptive immune response is important for many viral pathogens and very important for immunization strategies

Cytokines and the innate response to a viral infection

Innate Viral Interfering Activity is Discovered in Cultured Cells

(1950s)

X

Fractionating Viral Interfering Activity Leads to the Discovery of Interferons

(IFNs)

Leukocyte IFNsFibroblast IFNImmune IFN

• a.k.a IFN-’s• most prevalent• made by all cells• > 10 members

• a.k.a IFN-• very potent• made by all cells• only one member

• a.k.a IFN-• critical for adaptive Immune• made by T-cells & NK cells• only one member

Type II IFN Type I IFN

P

STAT1

STAT1

P

P

P

P

P

P

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)

Type II IFN Signaling Paradigm

Gamma-activated sequence

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

Figure 2-3

Wound Infection: Innate Adaptive

Figure 2-5 part 1 of 2

Figure 2-8 part 1 of 2

Figure 2-39

Figure 2-15

QuickTime™ and aGIF decompressor

are needed to see this picture.

• 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).

Cytokines and the response to sepsis

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

Hours after LPS injection

Seru

m C

yto

kin

e L

evel

TNF-

o 1 3 6

IL-1 IL-12

Note, this is one of the few times you can meaningfully measure serum cytokine levels!!

Figure 2-46

IL-4 TNF- Trimer

TNF Monmer/Receptor MonomerFig. 2-38 IL4/IL4 Receptor

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

Top half of Fig. 2-47

V. Cytokines you need to know

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- IFN- (large family)

IL-1IL-18

LT-TNF-CD40LFasL

TGF- (very large family)

Chemokines (see Fig. 11.6)InflammatoryNon-inflammatory

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

Innate Adaptive

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Type I & IICytokine Receptors

(Hematopoietin R.)

Toll (TLR) /IL-1Receptors

TNF RelatedReceptors

TGF-Receptors

ChemokineReceptors