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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
10. 10. 18

JEONG Young Jee

overiew
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
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.

1 introduction
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.

2 rapid cytokine production by effectors
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

2 rapid cytokine production by effectors1
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.

2 rapid cytokine production by effectors2
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

2 rapid cytokine production by effectors3
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.

2 rapid cytokine production by effectors4
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

3 distinct biochemical responses to tcr engagement in th2 effectors
3. Distinct biochemical responses to TCR engagement in Th2 effectors
  • TCR-driven signaling components

Fig 1.

Signaling differences

in Th1 and Th2 effectors

3 distinct biochemical responses to tcr engagement in th2 effectors1
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

3 distinct biochemical responses to tcr engagement in th2 effectors2
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

3 distinct biochemical responses to tcr engagement in th2 effectors3
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.

4 signal requirements for th2 cells to exert effector function
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

4 signal requirements for th2 cells to exert effector function1
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.

4 signal requirements for th2 cells to exert effector function2
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

4 signal requirements for th2 cells to exert effector function3
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

4 signal requirements for th2 cells to exert effector function4
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.

4 signal requirements for th2 cells to exert effector function5
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

5 regulation at sites of inflammation
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

5 regulation at sites of inflammation1
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.

5 regulation at sites of inflammation2
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

6 conclusion
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