The research progress of CD4 CD25 regulatory T cell

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The research progress of CD4CD25regulatory T
cell
and

• The mechanism it participates in tumor immunity

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• Team members ??? ???
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History

• This kind of cells was first found by Mukherji in
  1986.

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history

• The cells were first named by Sakaguchi in 1995

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A special CD4 T cell

• Treg is a special CD4 T cell
• Most CD4 T cells belong to Th1 or Th2
• But 5--10 of CD4T cells belong to neither one
  which is called CD4 CD25 regulator T cells

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Treg Suppress the outgrowth of potentially
pathogenic self-reactive T cells (conventional T
cells)
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Increased Tregs Increase in Solid Tumors
Tumor Treg Site N Ref
NSCLC CD4CD25 TIL 11 Woo
Ovarian CD4CD25 Ascites 9 Woo
Breast CD4CD25 TIL, LN 35 Liyanage
Pancreas CD4CD25 TIL, LN 30 Liyanage
Melanoma CD4CD25 Met LN 12 Viguier JI 2004
GI (gastric, colon, pancreas, esoph, liver) CD4CD25hi PBMC 149 Sasada
GI (gastric, esoph) CD4CD25 PBMC, TIL 30 Ichihara
GI (gastric, esoph) CD4CD25 PBMC 114 Kono K
Ovarian CD4CD25 Ascites 104 Curiel
Head and Neck CD4CD25hi PBMC 24 Schaefer
Hepatocellular CD4CD25hi PBMC 84 Ormandy
Ovarian FoxP3 mRNA Tumor Bx 99 Wolf

• In most cases Treg suppressive function is
  confirmed in a subset of pts.
• Correlations between stage, prognosis, Tx in some
  studies e.g. gastric

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Source of normal Treg
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Source of normal Treg

• 1. As a function-specific T cell subpopulation,
  Treg developed from thymus directly.

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Source of normal Treg

• 2. Treg developed from peripheral lymph organ.

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Induced Treg
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Character

• CD25 is symbol of activation.
• FOXP3 is the specific mark.

• .

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Molecular Features of Treg cells
Molecular Marker Function
CD4 -Binds MHC class II -Expressed on Th cells
CD25 -Expressed on most Treg cells
CD3 -Ensures expression of TCR
GITR -Negative signaling -Required for survival
CTLA-4 -Binds CD80/CD86 -Antagonizes effects of CD28 to CD80/86
CCR7 -Mediates migration of Treg cells back to lymph nodes
Foxp3 -Required for differentiation and function of Treg cells
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• NOTE!
• There are no known cell surface molecules that
  uniquely distinguish the CD4 Treg cells from
  conventional activated CD4 T cells!

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CD4CD25Tregs
FACS
Microscopy
Co-culture
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gt90
Foxp3
CD25
CD25
Foxp3
CD4
CD25

• In vivo
• Maintain immune tolerance
• Inhibit autoimmunity
• prevent transplant rejection
• Interfere with anti-cancer immunity
• Potential in immune deficiency

• In vitro
• 5-10 of CD4 T cells
• Anergic to TCR stimulation
• Suppress T cell proliferation

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The Treg cell phenotype

• CD4
• Co-receptor for TCR recognition of MHC II/Ag
• CD25 IL-2Ra
• IL-2R component, confers high affinity binding to
  IL-2Rbg
• Key TR growth factor
• CTLA-4 cytotoxic T lymphocyte Ag-4
• Binds to B7s (CD80/86) on APC, acts as
  co-stimulatory molecule for TR (blocking CTLA-4
  inhibits TR)
• GITR glucocorticoid induced TNF related protein
• Ligation inhibits TR function (agonist inhibit
  TR, blocking augments TR)
• FoxP3
• Forkhead/winged-helix TF critical for TR activity
  and development
• Unlike surface markers / receptors, TE do not
  express FoxP3

Foxp3
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Molecular mechanism of CD4CD25 inhibiting tumor
immunity

• Two classes on its effect way

?.Inhibition dependents on cytokines
?.Inhibition through cell-cell contact
Act on effector T cells
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The former include inhibition induced by TGF-ß
and IL-10 signal pathway
the latter is mainlyreduced by CTLA-4.
DC is an important cell in CD4CD25Foxp3regulata
ry inhibition
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• CD25 and IL-2 signal pathway
• TGFßand IL-10 signal path
• Cell adhesion inhibition associated with CTLA-4
• Inhibit expression of DC

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TUMOR
25
TUMOR
APC
CD4
CD8
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APC
CD4
CD8
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CD4 Treg
CD8 Treg
APC
CD4
CD8
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CD4 Treg
CD8 Treg
APC
CD4
CD8
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CD4 Treg
CD8 Treg
Advantage!
TUMOR
APC
CD4
CD8
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CD8 Treg
CCL22
TUMOR
APC
CD4
CD8
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CD8 Treg
Advantage!
CCL22
TUMOR
APC
CD4
CD8
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That is all. Thank you!
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CD25 and IL-2 signal pathway

• CD25 , main antigen on surface of Treg cell,
  a-chain of IL-2R.
• IL -2 is mainly secreted by effector T cell.Its
  competition is the main mechanism of inhibition
  IL-2R on
  effector T celldimer on Tregtrimer

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Secretion of IL-2 can increase expression of
IL-2R on Treg cells while decrease it on effector
Tcells.
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TGFßand IL-10 signal pathway

• TGF-ßacts to inhibit reaction and proliferation
  of lymphocyts, and inhibit the activation of Mf.
• EffcctorCD8T cellNK cell

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TGF-ßR TGF-ß
segment kinase domain
phosphorate
activate

gene expresson
SMAD
initiate
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• Inhibition of Treg cell on NK cell are performed
  by NKG-2D to reduce its toxic activity directly.

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IL-10 participates in Treg cell inhibition by
regulating co-stimulatory molecules on APC.
IL-10
Antigen cytokine
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Cell adhesion inhibition associated by CTLA-4

• Activation of naïve T cells
• Peptide-MHC TCR
• B7 CD28

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B7
CTLA-4
CD28
stimulate
inhibit
APC
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• CTLA-4 has a much higher avidity for binding B7
  family members than that does CD28 and are
  expressed more widely in the body.
• Binding of CTLA-4 to B7 on DC expression of
  IDO(indoleamine 2,3-dioxygenase ) on DC, Tregs
  activated by IDO markedly upregulated programmed
  cell death 1 ligand 1 (PD-L1) and PD-L2
  expression on target DCs, and the ability of
  Tregs to suppress target T cell proliferation can
  be abrogated by antibodies against the programmed
  cell death 1/PD-L (PD-1/PD-L) pathway.

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Inhibit expression of DC

• NF-Kb
• (CD40,CD80\CD86,IL-12,TNF-a,CCL5)
• Cell-cell contact
• cytokine TGF-ß, IL -10

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DCs may induce T cell tolerance to tumors.
Tumor cells
infection
Tumor cells
IL-10
IL-10, VEGF
inflammation
Lack of inflammation
IL-10R
Tolerogenic DC
STAT3
Down regulation of co-stimulation
Tumor-induced Treg
effector T cells