2. Lectures 12 Cytokines and Immune Response September 24, 2004 Chris Schindler cws4@columbia.edu Reading: Janeway - as indicated Abbas - Chapter 11

3. 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

4. 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

5. Properties of Cytokines Abbas: Chpt. 11; Fig. 11.2

6. 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

7. For adaptive CD8 immunity An innate response

8. Figure 2-39

9. Biological actions of TNF Abbas: Chpt. 11 New Anti-inflammatory Agents Remicade (infliximab) Anti-TNF Enbrel (etanercept) TNF-Trap Kineret (anakinra) rIL1-RA

10. 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

11. Figure 8-24

12. Figure 8-10

13. IL-2

14. Figure 8-24

15. Most of Fig. 8-27

16. Most of Fig. 8-31

17. Important Th1 effector cytokines

18. Figure 8-19

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.

20. Let’s digress to review TCR signaling for an important clinical pearl!

21. TCR-mediated Signal Transduction: A Tyrosine Kinase Cascade Abbas & Lichtman, Fig. 8-7, p. 175

22. 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.

23. IFN-  is considered the Th1 signature cytokine.

24. IL-4, IL-5 and IL-6 are Th2 cytokines and promote humoral immunity

25. IL-10 and TGF-  are also Th2 important effector cytokines that potently antagonize cellular immunity. IL-4is the signature IL-4 is the signature Th2 effector cytokine

26. Figure 9-6

27. Figure 9-7

28. Polarization of CD4 + T-cells into functional Th1 and Th2 subsets Th 0 IL-5 IL-4 IL-6 Th 1 Th 2 IL-2 IFN-  IL-12 IL-4 TNF “The Allergic Limb” “The Autoimmune Limb” Naïve CD4 + T-helper DC

29. - Defense against parasites - Ab production & class switch Allergy Graft-vs-host disease Rheumatoid arthritis Type I Diabetes mellitus Multiple sclerosis Pathophysiology of the balance between Th1 and Th2 Th1Th2 - Defense against virus & intra- cellular pathogens - Anti-tumor immunity DTH

30. Figure 8-32

31. Chemokines

32. Chemokines signal through G protein- coupled receptors making them desirable drug targets

33. Leukocytes express unique sets of chemokines receptors allowing them to be targeted to the appropriate tissues

34. **CCL2 CCL5 CX 3 C **CXCL8 CXCL3 CXCL8 **CXCL7 FYI - some of the chemokine leukocyte specific activities Non-inflammatory (i.e., development/homing vs. inflammatory chemokines CCL3 **CXCL1,2,3CXCL1,2,3 CXCL10 CXCL10 (th1) CXCL12CCL3 CCL3 (th1) CCL4 CCL2CCL2 (th2) CCL5 **CCL5 **CCL18 XCL1 ** Activating chemokine

35. Chemokines are much more than just chemoattractants CXCL12 CXCR4

36. Chemokine Redundancy Abbas: Chpt. 11

37. Figure 2-41

38. Of Note..... Two chemokine receptors serve as co-receptors for HIV infection (CXCR4 and CCR5)Two chemokine receptors serve as co-receptors for HIV infection (CXCR4 and CCR5)

39. 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?

40. Cytokine Receptor Classes Abbas: Chpt. 11