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The research progress of
CD4+CD25+regulatory T cell
The mechanism it participates The mechanism it participates in tumor immunityin tumor immunity
425
1
0011 0010 1010 1101 0001 0100 1011
History• This kind of cells was first fou
nd by Mukherji in 1986.
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 CD4+T cells belong to neither one which is called CD4+ CD25+ regulator T cells
TTregreg: Suppress the outgrowth of : Suppress the outgrowth of potentially pathogenic self-reactive T potentially pathogenic self-reactive T
cells (conventional T cells)cells (conventional T cells)
MHC II
TCR
Adapted from: Wood, K.J. and Sakaguchi, S. (2003) Nat Rev Immunol 3, 199-210
Conventional T cell
Increased Treg’s Increase in Solid TumorsTumor Treg Site N Ref
NSCLC CD4+CD25+ TIL 11 Woo
Ovarian CD4+CD25+ Ascites 9 Woo
Breast CD4+CD25+ TIL, LN 35 Liyanage
Pancreas CD4+CD25+ TIL, LN 30 Liyanage
Melanoma CD4+CD25+ Met LN 12 Viguier JI 2004
GI (gastric, colon, pancreas, esoph, liver)
CD4+CD25hi PBMC 149 Sasada
GI (gastric, esoph) CD4+CD25+ PBMC, TIL 30 Ichihara
GI (gastric, esoph) CD4+CD25+ PBMC 114 Kono K
Ovarian CD4+CD25+ Ascites 104 Curiel
Head and Neck CD4+CD25hi % PBMC 24 Schaefer
Hepatocellular CD4+CD25hi 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
Source of normal Treg
1. As a function-specific T cell subpopulation, Treg developed from thymus directly.
CD3‾CD4+ CD8‾ TCR‾ CD3‾CD4‾CD8+ TCR‾
CD3LOWCD4‾CD8+ TCRLOW
CD3+ CD4+ CD8+ TCR+
CD3+ CD4+ CD8‾ TCR+ CD3+ CD4‾ CD8+ TCR+
CD3+ CD4+ TCR+ CD3+ CD8+ TCR+
CD3+ CD4+ CD25+T cell
CD3+CD4+CD25+Tcell
CD3+ CD4‾ CD25+ T
CD3+ CD4‾ CD25+ T
CD3+ CD4‾ CD25+ T
CD3+ CD25++T
CD3‾CD4‾/LOW CD8‾ TCR‾
CD3‾CD4‾/LOW CD8‾ TCR‾
被膜
被膜下区
皮质
骨髓
髓质
胸腺小叶
Molecular MarkerMolecular Marker FunctionFunction
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
NOTE!There are no known cell surface molecules that
uniquely distinguish the CD4+ Treg cells from conventional activated CD4+ T cells!
CD25
CTLA-4GITR CD4+CD25+
RegulatoryT cell
CD4+CD25+Tregs
In vivo Maintain immune tolerance Inhibit autoimmunity prevent transplant rejection Interfere with anti-cancer immunity Potential in immune deficiency
40
30
20
10
0
3H
up
take
(x1
0-3)
CD25– CD25+ CD25–
+CD25+
•In vitro• 5-10% of CD4+ T cells•Anergic to TCR stimulation•Suppress T cell proliferation
100 101 102 103 104
FL1-Spl/PBS/CD4
L090905.005
R2
100 101 102 103 104
FL4-Spl/PBSCD25
L090905.005
CD4
CD
25
Fo
xp3
FACS
CD25
CD25 Foxp3
Microscopy Co-culture
10% >90%
Treg
CD4 CD25
CTLA-4GITR
The Treg cell phenotype CD4
Co-receptor for TCR recognition of MHC II/Ag
CD25 IL-2R
IL-2R component, confers high affinity binding to IL-2R
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 fo
r TR activity and development
Unlike surface markers / receptors, T
E do not express FoxP3
Foxp3
Molecular mechanism of Molecular mechanism of CD4+CD25+ inhibiting tumor CD4+CD25+ inhibiting tumor
immunityimmunity• Two classes on its effect wayTwo classes on its effect way
Ⅱ.Inhibition through cell-cell contact
Ⅰ.Inhibition dependents on cytokines
Act on effector T cells
DC is an important cell in CD4+CD25+Foxp3+regulatary
inhibition
DC is an important cell in CD4+CD25+Foxp3+regulatary
inhibition
The former The former include include inhibition inhibition induced by induced by TGF-β and IL-TGF-β and IL-10 signal 10 signal pathwaypathway
The former The former include include inhibition inhibition induced by induced by TGF-β and IL-TGF-β and IL-10 signal 10 signal pathwaypathway
the latter is the latter is mainlyredumainlyreduced by CTced by CTLA-4LA-4..
the latter is the latter is mainlyredumainlyreduced by CTced by CTLA-4LA-4..
* CD25 and IL-2 signal pathway
* TGFβand IL-10 signal path *
Cell adhesion inhibition associated with CTLA-4
* Inhibit expression of DC
CD25 and IL-2 signal pathwayCD25 and IL-2 signal pathway
• CD25 , main antigen on surface of Treg CD25 , main antigen on surface of Treg cell, α-chain of IL-2R.cell, α-chain of IL-2R.
• IL -2 is mainly secreted by effector T cell.IL -2 is mainly secreted by effector T cell.Its competition is the main mechanism oIts competition is the main mechanism of inhibition IL-2f inhibition IL-2R on effector T cell:dimer on Treg:trimR on effector T cell:dimer on Treg:trimer er
Secretion of IL-2 can increase expression of IL-2R on Treg cells while decrease it on effector Tcells.
Secretion of IL-2 can increase expression of IL-2R on Treg cells while decrease it on effector Tcells.
TGFβand IL-10 signal pathwayTGFβand IL-10 signal pathway
• TGF-βacts to inhibit reaction and proliferTGF-βacts to inhibit reaction and proliferation of lymphocyts, and inhibit the activation of lymphocyts, and inhibit the activation of Mφ.ation of Mφ.
Effcctor:CD8+T cellEffcctor:CD8+T cell && NK cellNK cell
IL-10 participates in Treg cell inhibition by regulating co-stimulatory molecules on APC.
IL-10 participates in Treg cell inhibition by regulating co-stimulatory molecules on APC.
Antigen cytokine
CD40
CD80/CD86
IL-10
Cell adhesion inhibition Cell adhesion inhibition associated by CTLA-4associated by CTLA-4
• Activation of naïve T cells :Activation of naïve T cells :
Peptide-MHC + TCRPeptide-MHC + TCR
B7 + CD28B7 + CD28
• 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.
Inhibit expression of DCInhibit expression of DC
• NF-KbNF-Kb
(CD40,CD80\CD86,IL-12,TNF-a,CCL5) (CD40,CD80\CD86,IL-12,TNF-a,CCL5)
• Cell-cell contact Cell-cell contact
• cytokine: TGF-β, IL -10cytokine: TGF-β, IL -10