Lectures 12

Cytokines and Immune Cytokines and Immune ResponseResponse

September 24, 2004

Chris Schindlercws4@columbia.edu

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