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.
JEONG Young Jee
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
Cross regulation among the factors that are involved in Th1 and Th2 differentiation
Zhu J, PaulWE. Blood 2008;112:1557–69.
: 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.
: 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
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
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.
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
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.
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
in Th1 and Th2 effectors
Th2 : ↓calcium flux & ↓TCR-triggered tyrosine phosphorylation
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
: important amplifier of calcium flux
-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
: 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.
⇒NFATc1, NFκB p50, GATA3 ⇒ IL-4
Possible ITK-dependent control points in Th2 effector function
- 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.
: 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
⇒ ↑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
: regulate Th2 effector function
at multiple levels
: 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.
- 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
: spatially segregated
-> inflammatory milieu edits cytokine repertoire via effector functions
(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
: 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.
1) Th1 effectors
: toll-like receptor, IFNγ-producers
2) Th2 effectors
: TLR ligands, CpG
: TGFβ in Th2 cells
Autoregulation in Th1 cells
via regulation of gene expression.
⇒ site-directed targeting
&selective therapeutic strategy