The g c Family of Cytokines Prof. Warren J. Leonard M.D.

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1 The Family of Cytokines Chief, Laboratory of Molecular Immunology Director, Immunology Center National Heart, Lung, and Blood Institute National Institutes of Health Department of Health and Human Services 1 Today s talk Today, I will discuss: Some general features of cytokines, including the concepts of cytokine and cytokine receptor pleiotropy and redundancy The family of cytokines and its relationship to X-linked severe combined immunodeficiency Some specific features of family cytokines 2 family cytokines:, IL-4, IL-7, IL-9, IL-15, and 1 3 Leonard WJ. Nat Rev Immunol. 2001; 1:

2 cytokines are important because of their broad activities in many biological processes, their relationship to inherited forms of human immunodeficiency, and also for historical reasons 4 5 Cytokines The term cytokine was coined by Stanley Cohen in 1974 to refer to molecules produced by one cell (hence cyto ) that act (hence kine ) on the same or another cell; Many cytokines are growth factors or hormones of the immune and hematopoietic systems Today, I will not discuss IL-1 or TNF family cytokines, TGFb, or chemokines, and type II cytokines, which include interferons and the IL-10 family of cytokines; Instead, I will focus on a subtype of type I cytokines, namely those that share the common hain,, including, IL-4, IL-7, IL-9, IL-15, and 1 Type I and type II cytokines Type I cytokines include many interleukins (e.g.,, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 21, 23, 27, 31, 35), as well as GM-CSF, G-CSF, EPO, TPO, prolactin, growth hormone, and stem cell factor; They are structurally four a-helical bundle cytokines Type II cytokines are interferons and structurally related molecules such as IL-10, 19, 20, 22, 24, 26, 28 and 29 Note that Th1 and Th2 designations of T helper cytokines are different; IL-4 is a type I cytokine that is a Th2 cytokine whereas IFNg is a type II cytokine that is a Th1 cytokine; (parenthetically, Th17 cells produce IL-17 which has a neurotrophin cysteine-knot, rather than a type I or type II cytokine structure) 6 2

3 Type I cytokines are either short-chain or long-chain four a-helical bundle structures N C N C Short chain cytokines (helices 15 aa long) Examples: cytokines sharing b c or 7 Lonhain cytokines (helices 25 aa long) Examples: GH, EPO, Prl, cytokines share gp130 GH/GHR complex 8 de Vos AM, Ultsch M, Kossiakoff AA. Science 1992; 255: family cytokines:, IL-4, IL-7, IL-9, IL-15, and 1 9 Leonard WJ. Nat Rev Immunol. 2001; 1:

4 receptors three chains, three affinities of receptor binding Affinity Chains Kd(M) Low a 10-8 Intermediate b High a + b Ra Low affinity High affinity Rb Rb Rg Activation Clonal expansion 11 MHC Antigen-presenting cell or B cell TCR TCR triggering Resting T cell NFATc NFATn Ra Activated T cell Ra Differentiation Effector (T H1, T H2, T H17) Slide Provided by: Dr. K. Christopher Garcia Professor, Stanford University and Howard Hughes Medical Institute The high affinity receptor a b 12 4

5 family cytokines:, IL-4, IL-7, IL-9, IL-15, and 1 13 Leonard WJ. Nat Rev Immunol. 2001; 1: The expanded family of cytokines A IL-4 IL-7 IL-9 IL-15 1 Ra IL-15Ra Rb IL-7Ra IL-9Ra Rb 1Ra IL-4Ra B IL-4 IL-13 C IL-7 TSLP IL-13Ra1 IL-13Ra1 TSLPR 14 IL-4Ra IL-4Ra IL-7Ra IL-7Ra mutations result in X-linked severe combined immunodeficiency in humans 15 Leonard WJ. Nat Rev Immunol. 2001; 1:

6 Basis for T, NK, and B-cell defects in XSCID 1. T-cell defect due to lack of IL-7R-dependent signaling 2. NK-cell defect due to defective IL-15-mediated activation of STAT5 proteins 3. B cells are normal in number but non-functional; This results from defective signaling of IL-4 and 1 16 Why share? 17 Leonard WJ. Nat Rev Immunol. 2001; 1: Why share? (2) 1. Basis for shared actions? 2. Basis for competition for a limited resource? 18 6

7 Why share? (3) 19 Leonard WJ. Nat Rev Immunol. 2001; 1: Cytokine pleiotropy: multiple actions of a single cytokine is a T-cell growth factor, mediates AICD, augments NK-cell cytolytic activity, increases the activity of LAK cells, can increase Ig production, is a key factor for development of Treells, drives CTL activity, and can prime for Th1 and Th2 differentiation Pleiotropic actions for cytokines are common and perhaps even the rule, in part resulting from expression of the same cytokine receptors in multiple lineages Cytokine redundancy: more than one cytokine have similar actions 20 Cytokine pleiotropy and redundancy, IL-4, IL-7, IL-9, IL-12, IL-15, 1, and GM-CSF can act as T-cell growth factors IL-4 and IL-13 act through the identical receptor on fibroblasts Are similar actions truly identical actions in vivo? Cytokine receptor pleiotropy and redundancy Cytokine receptor pleiotropy: a protein acting as a receptor component for more than one cytokine Shared components for many type I cytokines (e.g., Rb, ) Cytokine receptor redundancy: two or more cytokine receptors mediating the action of a single cytokine can signal via intermediate and high-affinity receptors IL-4 can signal via IL-4Ra/ or IL-4Ra/IL-13Ra1 However, it is not certain that the signals induced through each type of receptor are identical 21 7

8 activates multiple signaling pathways (JAK-STAT, PI 3-K, MAPK) a b Raf1 Ras SOS Grb2 MEK MAPK Jak1 Shc Y338 Jak3 Y392 STAT Src Rsk? Y510 STAT STAT STAT STAT Akt PI 3-K Rap p70 S6K A Rsk Gene expression Nucleus 22 A A TATA A Biological responses STAT STAT A TATA Mutations in or result in similar clinical and immunological phenotypes 1R Rb IL-9R IL-7R IL-4R Rb 1 IL-15 IL-9 IL-7 IL-4 XSCID 23 Pleiotropic use of JAKs: only 4 JAKs but many cytokines IFNs IFNa IFNg, TYK2, JAK2 gp130 family IL-6, IL-11, OSM, LIF, CNTF, CT1, NNT-1 family, IL-4, IL-7, IL-9, IL-15, 1, JAK2, TYK2, b c family 24 IL-3, IL-5, GM-CSF Growth hormone, prolactin, EPO, TPO IL-10 IL-12 JAK2 JAK2, TYK2 JAK2, TYK2 8

9 Causes of T - B + NK - and T - B + NK + SCID IL-4 IL-7 IL-9 IL-15 1 IL-7 (Noguchi et al., Cell 1993) IL-7Ra X X (Macchi et al., Nature 1995) (Russell et al., Science 1995) X (Puel et al., Nature Genet.1998) 25 T- B + NK - SCID T - B + NK + SCID What is the basis for signaling specificity? 1. Where and when the cytokines are produced 2. The cellular lineages on which the receptors are expressed and temporally when they are expressed 3. Distinctive combinatorial activation of signaling pathways 26 IFNs IFNa, IFNb IFNg Pleiotropic use of STATs STAT1, STAT2 STAT1 gp130 family 27 IL-6, IL-11, OSM, LIF, CNTF, CT1, NNT-1 family, IL-7, IL-9, IL-15 IL-4 1 b c family IL-3, IL-5, GM-CSF Growth hormone, prolactin, EPO, TPO IL-10 IL-12 STAT3 STAT5A, STAT5B > STAT3 STAT6 > STAT5A, STAT5B STAT3 > STAT1, STAT5A, STAT5B STAT5A, STAT5B STAT5A, STAT5B STAT3 STAT4, STAT3 9

10 Produced by: Summary of sources of family cytokines and TSLP, how they signal, and target cells 1 CD4 + T NKT IL-15 Monocytes DCs Epithelial cells IL-4 NKT Eosinophils Mast cells IL-9 IL-7 Stromal cells Epithelial cells Fibroblasts TSLP Stromal cells Epithelial cells Fibroblasts Mast cells 1 IL-15 IL-4 IL-9 IL-7 TSLP TSLPR 1R Ra Rb IL-15Ra Rb IL-4Ra IL-9Ra IL-7Ra IL-7Ra Activates:? STAT3 STAT1 STAT5 STAT5 STAT1 STAT3 STAT5 STAT6 STAT5 STAT5 STAT5 STAT1 STAT3 STAT5 Target cells: 28 B cells NK cells DCs B cells NK cells NK cells B cells NK cells Mast cells Basophils Mast cells B cells Epithelial cells DCs Eosinophils B cells DCs NK Mast cells 1. T-cell growth factor 2. Differentiation of Treells 3. Development of CTL 4. Boosts cytolytic activity of NK cells and LAK cells 5. Mediates AICD 6. Promotes Ig production 7. Can prime for Th1 and Th2 differentiation via its induction of IL-12Rb2 and IL-4Ra 8. Inhibits Th17 differentiation by inhibiting IL6R and gp130 and inducing T-bet 29 Actions of Therapy related to 1. Anti-cancer agent (e.g., melanoma, renal cell carcinoma) 2. Immunosuppressive drugs such as cyclosporine A cyclosporine A and FK506 suppress production of 3. Daclizumab is a humanized anti-r-alpha antibody that blocks binding to high affinity receptors, is now being used to prevent renal allograft rejection, in multiple sclerosis, and in a range of other diseases 30 10

11 Activities of IL-4 1. Critical for driving Th2 differentiation 2. Vital roles in allergic disease, asthma, and helminth infection 3. Critical for IgE production 4. Induces expression of FceRI and IL-4R 5. Drives Ilass switch 31 Activities of IL-7 1. Critical for development of in mice and humans and B cells in mice 2. Contributes to the regulation of homeostasis of both naïve and memory, particularly related to CD8 T cell homeostasis 3. Potently induces BCL2 and PI 3-kinase, while diminishing BAD and BAX, thereby promotinell survival 4. Down-regulates expression of its own receptor 32 Activities of IL-9 1. T cell growth factor 2. Mast cell growth factor 3. Goblet cell hyperplasia 4. Promotion of allergic disease 33 11

12 Activities of IL Critical for the development of NK cells and contributes to their cytolytic activity 2. Critical role for CD8 T cell homeostasis, particularly for memory cells 3. T cell growth factor 4. Mast cell growth factor 5. Goblet cell hyperplasia 6. Promotion of allergic disease Pleiotropic actions of 1 IFNg Th1 Th2 Th17 IL-17 1 Cytotoxicity NKT Proliferation Anti-tumor activity 35 DC APC function B 1 Proliferation/apoptosis Plasma cell differentiation Ig production Spolski and Leonard, Annu. Rev. Immunol. 26: 57-79, 2008 CD8 Cytotoxicity Proliferation/survival Anti-tumor activity Cytotoxicity NK Proliferation Anti-tumor activity Related to B cells Activities of 1 A. Drives production of BCL6 and BLIMP1, driving differentiation to germinal center B cells and terminal differentiation to plasma cells, depending on the context B. Pro-apoptotic for incompletely activated B cells, which potentially might be autoreactive; parallel to the role of in AICD? C. Promotes Ilass switch to IgG1 and IgG3 but inhibits IgE production 2. Cooperates with IL-15 or IL-7 to drive CD8 T cell proliferation 3. Promotes Th17 differentiation via a signalinascade involving IL-6 and 3 4. Can activate NK cells but be pro-apoptotic for them 5. Negative regulator of DC activity 12

13 Clinical potential of 1 1. Anti-cancer agent in phase 2 clinical trials for melanoma and renal cell carcinoma 2. Given that 1 can promote autoimmune disease, blocking 1 may be effective in such settings 37 Cells that express receptor chains for cytokines 38 family cytokines:, IL-4, IL-7, IL-9, IL-15, and 1 39 Leonard WJ. Nat Rev Immunol. 2001; 1:

14 Thanks very much for your attention! Dr. Leonard is supported by the Intramural Research Program National Heart, Lung, and Blood Institute, NIH