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10. 10. 18 JEONG Young Jee

10. 10. 18 JEONG Young Jee. Overiew. T-cell activation & differentiation. B.J. Marsland and M. Kopf, Trends Immunol 29 (2008), pp. 179–185.  T-cell activation and differentiation. CD4 + T-cell dependence of CD8 + T cells. Overview. Cytokine program of CD4+ T cells.

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10. 10. 18 JEONG Young Jee

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  1. 10. 10. 18 JEONG Young Jee

  2. Overiew • T-cell activation & differentiation B.J. Marsland and M. Kopf, Trends Immunol 29 (2008), pp. 179–185.  T-cell activation and differentiation CD4+ T-cell dependence of CD8+ T cells

  3. Overview • Cytokine program of CD4+ T cells Cross regulation among the factors that are involved in Th1 and Th2 differentiation Zhu J, PaulWE. Blood 2008;112:1557–69.

  4. 1. Introduction • CD4+ T cell subsets : Th1, Th2, Th17 & iTreg “Signaling requirements for cytokine expression” Summary of the 4 CD4 T helper cell fates : functions, products, transcription factors, and cytokines critical for their fate determination J. Zhu and W.E. Paul, CD4 T cells: fates, functions, and faults, Blood 112 (2008), pp. 1557–1569.

  5. 2. Rapid cytokine production by effectors • Effector & memory cells : secrete high level of effector cytokines A. Effector cells - chromatin remodeling in IL-4 locus : CNS-1, DHS site VA & CIRE 1) CNS-1 regulatory region • wild-type (filled squares), CNS-1+/- (open circles) • CNS-1-/- (open triangles) Numbers of IL-4–expressing mast cells are not altered by the absence of CNS-1 Positive and negative regulatory elements within Il4/Il13 loci and their binding to transcription factors Amounts of IL-4 mRNA in CNS-1–/– CD4+ T cells Zhu J, PaulWE. Blood 2008;112:1557–69. Mohrs M, Blankespoor CM, Wang ZE, Loots GG, Afzal V, Hadeiba H, et al. Nat Immunol 2001;2:842–7

  6. 2. Rapid cytokine production by effectors 2) Dnase I hypersensitivity (DHS) site VA & CNS-2 region The V/VA region is essential for IL-4 transcription by mast cells Solymar DC, Agarwal S, Bassing CH, Alt FW, Rao A. Immunity 2002;17:41–50.

  7. 2. Rapid cytokine production by effectors 3) GATA3 & CIRE for IL-4, promoter of IL-5, IL-13 Molecular requirement for the initiation and the maintenance of Th2 cell identity Both IL-4-dependent and IL-4-independent TH2 differentiation is considerably impaired in cells in which Gata3 has been deleted by hCre-GFP-RV. Nakayama T, Yamashita M. Curr Opin Immunol 2008;20:265–71

  8. 2. Rapid cytokine production by effectors B. Memory cells 1) MLL (mixed-lineage leukemia) gene The Ability to Produce Th2 Cytokines in MLL+/2 Effector and Memory Th2 Cells Yamashita M, Hirahara K, Shinnakasu R, Hosokawa H, Norikane S, Kimura MY, et al. Immunity 2006;24:611–22.

  9. 2. Rapid cytokine production by effectors 2) NFAT Increased levels of NFATc1 and NFATc2 in memory CD4+ T cells Dienz, S.M. Eaton, T.J. Krahl, S. Diehl, C. Charland and J. Dodge et al., Proc Natl Acad Sci USA 104 (2007), pp. 7175–7180

  10. 3. Distinct biochemical responses to TCR engagement in Th2 effectors • TCR-driven signaling components Fig 1. Signaling differences in Th1 and Th2 effectors

  11. 3. Distinct biochemical responses to TCR engagement in Th2 effectors • Calcium flux Th2 : ↓calcium flux & ↓TCR-triggered tyrosine phosphorylation • Cell surface molecules Fowell DJ, Magram J, Turck CW, Killeen N, Locksley RM. Immunity 1997;6:559–69. F. Balamuth, D. Leitenberg, J. Unternaehrer, I. Mellman and K. Bottomly, Immunity 15 (2001), pp. 729–738 Impaired Th2 development in CD4/2 mice infected with N. brasiliensis Distinct Raft Recruitment Pattern of TCR and CD45 in Th1 and Th2 Cells

  12. 3. Distinct biochemical responses to TCR engagement in Th2 effectors • Signaling molecules TEC-family kinase : important amplifier of calcium flux -ITK -RLK → IFNγ ▶▼Itk is upregulated and Rlk is downregulated during Th2 differentiation E.M. Schaeffer, G.S. Yap, C.M. Lewis, M.J. Czar, D.W. McVicar and A.W. Cheever et al., Nat Immunol 2 (2001), pp. 1183–1188. A.T. Miller, H.M. Wilcox, Z. Lai and L.J. Berg, Immunity 21 (2004), pp. 67–80 ◀Decreased activation of NFATc and NFATp in Rlk-/-Itk-/- T lymphocytes

  13. 3. Distinct biochemical responses to TCR engagement in Th2 effectors • Immunological synapse ; TCR, PKCθ, CD45 & talin • ? Directional secretion : synaptical or multidirectional secretion Distinct colocalization patterns of TCR and GM1 ganglioside at the APC contact zone in intact Th1 and Th2 cells F. Balamuth, D. Leitenberg, J. Unternaehrer, I. Mellman and K. Bottomly, Immunity 15 (2001), pp. 729–738.

  14. 4. Signal requirements for Th2 cells to exert effector function • ITK, PKCθ, SAP, SLAM, LAT & VAV1 ⇒NFATc1, NFκB p50, GATA3 ⇒ IL-4 Fig 2. Possible ITK-dependent control points in Th2 effector function

  15. 4. Signal requirements for Th2 cells to exert effector function • ITK (interleukin-2-inducible T cell kinase) - member of TEC family tyrosine kinase -activate phospholipase C (PLC)-γ1 ⇒ calcium flux, MAP kinase, NFAT Effector Th cell development in the absence of Itk Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, et al.Immunity 1999;11:399–409.

  16. 4. Signal requirements for Th2 cells to exert effector function • Transcriptional regulation -NFAT : essential for IL-2 production in memory T cells -Interferon regulatory factor (IRF)-4 : ↓Th2 cytokine production in naïve CD4+ T cells & ↑in Th2 effector cells -NFAT + IRF-4 ⇒ ↑IL-4

  17. 4. Signal requirements for Th2 cells to exert effector function • TCR stimulation ⇒ ↑translational efficiency -rRNA processing & post-translational regulation of RPS (ribosomal protein subunit)  Expression of Genes Encoding rRNA Processing Factors Is Increased by Stimulation of Th2 Effector Cells M. Asmal, J. Colgan, F. Naef, B. Yu, Y. Lee and M. Magnasco et al, Immunity 19 (2003), pp. 535–548

  18. 4. Signal requirements for Th2 cells to exert effector function ERK-MAPK pathway • EKR : regulate Th2 effector function at multiple levels • p38 (MAP kinase) : promote cytokine production in Th2 effector cells through IL-4 mRNA stability regulation  RRS1 mRNA Increases in Response to ERK-MAPK Signaling Staurosporine: PKC inhibitor PMA: PKC activator ionomycin : Ca++ -flux activator cyclosporine: Ca++-flux inhibitor M. Asmal, J. Colgan, F. Naef, B. Yu, Y. Lee and M. Magnasco et al., Immunity 19 (2003), pp. 535–548.

  19. 4. Signal requirements for Th2 cells to exert effector function • additional post-transcriptional control - ISR(integrated stress response) : optimize cytokine expression ⇒ protein biosynthesis, translation regulation in differentiating Th2 cells, ↑IRS → translational attenuation of cytokine mRNAs → no IL-4 protein

  20. 5. Regulation at sites of inflammation • High-level IL-4 protein production : spatially segregated -> inflammatory milieu edits cytokine repertoire via effector functions GFP+/huCD2+ (IL-4-secreting), GFP+/huCD2− (IL-4 competent but no secreting), GFP−/huCD2− (not competent for IL-4 production) K. Mohrs, A.E. Wakil, N. Killeen, R.M. Locksley and M. Mohrs, Immunity 23 (2005), pp. 419–429 Cytokine transcripts and protein production by huCD2+ and huCD2− GFP+ Th2 Cells

  21. 5. Regulation at sites of inflammation • Extrinsic factors : IL-33, TSLP(thymic stromal lymphopoietin), & TNFRSF(tumor necrosis receptor superfamily )  IL-33-Induced NF-κB Phosphorylation and MAPK Activation and TH2 Cytokine Production J. Schmitz, A. Owyang, E. Oldham, Y. Song, E. Murphy and T.K. McClanahan et al., Immunity 23 (2005), pp. 479–490.

  22. 5. Regulation at sites of inflammation • Pathogen itself 1) Th1 effectors : toll-like receptor, IFNγ-producers 2) Th2 effectors : TLR ligands, CpG • Additional level of control : TGFβ in Th2 cells Autoregulation in Th1 cells

  23. 6. Conclusion • Effector cells signal differently from naive counterparts. • Different effector cytokines require distinct signals for high-level production. • Stage-specific signaling controls effector function via regulation of gene expression. • Effector function is modulated. • Difference btw naive & differentiating cells ⇒ site-directed targeting &selective therapeutic strategy

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