sous populations lymphocytaires t cd4+ et cd8+ de type 1...
TRANSCRIPT
Sous populations lymphocytaires T CD4+ et CD8+ de type 1, type 2, type 17, type X …
CD4 Th1, Th2, Th17, ThX CD8 Tc1, Tc2, Tc17, TcX
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T cell subset plasticity
Jean-François Nicolas
Université Lyon1 / INSERM U1111 - CIRI / Hôpitaux de Lyon
Outline
1. T cell subsets in humans
2. Psoriasis: a Th17-mediated disease through
production of TNF- and IL-17
3. IL-17 and IL-17 targeting
4. Th17 and Th17 targeting
5. T cell plasticity
Many novel CD4+ T cell subtypes have been described in recent years
?
1986 Th1 vs Th2 model Mosmann TR, et al. J Immunol. 1986;136(7):2348–57.
1995 Regulatory T cells* Sakaguchi S, et al. J Immunol. 1995;155(3):1151–64.
2003 Th17 Aggarwal S, et al. J Biol Chem. 2003;278(3):1910–4.
2008 Th9 Veldhoen M, et al. Nat Immunol. 2008;9(12):1341–6.
2009 Th22 Eyerich S, et al. J Clin Invest. 2009;119(12):3573–85.
1990 2000 2010
Th1 Th2 Th22 Th9 Th17 Treg
1986 1995 2003 2008 2009
*"Suppressor cells" had been described in the late 1970s, but only identification of CD25+ enabled description
Specific CD4+ T cell populations develop from naïve T cells
Naïve
T cell
Th1 Th2 Th22 Th9 Th17 Treg
IFN-γ IL-12
IL-4 IL-2
TGF-β IL-2
TGF-β IL-4
TNF-α IL-6
in the presence of in the presence of
TGF-β (IL-1) IL-6, IL-21, IL-23
Duhen T, et al. Nat Immunol. 2009;10(8):857–63. Wong MT, et al. Immunol Cell Biol. 2010;88(6):624–31. Zhu J, Paul WE. Blood. 2008;112(5):1557–69.
T cell populations are principally defined by their cytokine profiles
Naïve
T cell
Th1 Th2 Th22 Th9 Th17 Treg
IFN-γ IL-12
IL-4 IL-2
TGF-β IL-2
TGF-β (IL-1) IL-6, IL-21, IL-23
TGF-β IL-4
TNF-α IL-6
IL-10 TGF-β IL-35
IL-22 IL-17A IL-17F TNF-α IL-21 IL-22
(IL-10)
IL-9 IL-10
TNF-α IFN-γ IL-2
(IL-10)
IL-4 IL-5 IL-13 IL-25 IL-10
in the presence of in the presence of
Duhen T, et al. Nat Immunol. 2009;10(8):857–63. Tan C, et al. J Immunol. 2010;185(11):6795–801. Zhu J, Paul WE. Blood. 2008;112(5):1557–69.
Each CD4+ T cell subtype has specific tasks in a normally functioning immune system
Th1 Th2 Th22 Th9 Th17 Treg
IFN-γ IL-12
IL-4 IL-2
TGF-β IL-2
TGF-β IL-4
TNF-α IL-6
Promotes cell-
mediated immunity and
phagocyte-dependent
protective responses
Naïve
T cell
Regulation of
immune
responses
Proposed to
promote
inflammation and
immune cell
proliferation Promotes humoral
immunity,
e.g. immunoglobulin
production
Promotes immune
response to specific
bacterial and fungal
infections
Context-dependent
up- or down-
modulation of
tissue response to
inflammation
in the presence of in the presence of
TGF-β (IL-1) IL-6, IL-21, IL-23
Crome SQ, et al. Clin Exp Immunol. 2010;159(2):109–19. Sakaguchi S, et al. J Immunol. 1995;155(3):1151–64. Goswami R, et al. J Immunol. 2012;188(3):968–75. Sanjabi S,
et al. Curr Opin Pharmacol. 2009;9(4):447–53.
CD4+ T cell populations have also been implicated in autoimmune or immune-mediated disorders
Th1 Th2 Th22 Th9 Th17 Treg
IFN-γ IL-12
IL-4 IL-2
TGF-β IL-2
TGF-β IL-4
TNF-α IL-6
Psoriasis, psoriatic
arthritis, rheumatoid
arthritis, Crohn's
disease
Naïve
T cell
Inappropriate
balance or
dysregulation
associated with
diseases, including
autoimmunity,
allergy and infection
Proposed role in
allergic disease
Atopic disease,
e.g. eczema, allergic
rhinitis, asthma
Psoriasis, psoriatic
arthritis, rheumatoid
arthritis, Crohn's
disease
Proposed role in inflammatory
and immune-mediated disease,
including psoriasis, rheumatoid
arthritis, Crohn's disease,
atopic dermatitis
in the presence of in the presence of
TGF-β (IL-1) IL-6, IL-21, IL-23
Brand S. Gut. 2009;58(8):1152–67. Brandt EB, Sivaprasad U. J Clin Cell Immunol. 2011;2(3):110. Kagami S, et al. J Invest Dermatol. 2010;130(5):1373–83. McInnes IB,
Schett G. N Engl J Med. 2011;365(23):2205−19. Nograles KE, et al. J Allergy Clin Immunol. 2009;123(6):1244–52. Nograles KE, et al. Nat Clin Pract Rheumatol. 2009;5(2):
83–91.Radstake TR, et al. Ann Rheum Dis. 2004;63(6):696–702. Soroosh P, Doherty TA. Immunology. 2009;127(4):450–8. Taams LS, et al. Immunology. 2006;118(1):1–9.
Zhang L, et al. J Clin Immunol. 2011;31(4):606–14. Zhang N, et al. Mol Cell Biochem. 2011;353(1-2):41–6.
Outline
1. T cell subsets in humans
2. Psoriasis: a Th17-mediated disease through
production of TNF- and IL-17
3. IL-17 and IL-17 targeting
4. Th17 and Th17 targeting
5. T cell plasticity
Psoriasis: = Dermatose Inflammatoire Chronique (érythémato-squameuse)
3-5% de la population
10% de formes graves
Psoriasis: = Dermatose Inflammatoire Chronique (érythémato-squameuse)
3-5% de la population
Patient avec poussées de psoriasis des coudes, des genoux
et du cuir chevelu depuis 2 ans
Efficacité des traitements sur les poussées
Ne prend pas de médicaments par ailleurs
Inflammation cutanée
(érythème) dermique et
épidermique
Prolifération accrue
des kératinocytes et
différenciation
altérée (squames)
Psoriasis = 2
anomalies
majeures...
... points d’impacts
des traitements
Psoriasis = Dermatose Inflammatoire Chronique (auto-immune) = par activation dans la peau de LT spécifiques d’auto-Ag épidermique
anti-CD3
Pathophysiology of psoriasis
Adapted from: Nestle FO, et al. N Engl J Med. 2009;361(5):496-509.
Predisposing factors
Disease initiation Disease maintenance
Adapted from: Nestle FO, et al. N Engl J Med. 2009;361:496-509;
The vicious cycle of psoriasis
DC-T cell-keratinocyte interactions drive the disease process and maintenance
Antimicrobial peptides
IL-1b
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
IL-17C
Th1
Th17
IL-23
IL-12 TNF- IFN-g
IL-17A IL-17F IL-21 IL-22
TNF-
Keratinocyte
Keratinocyte
NK T cell
Plasmacytoid dendritic cell
Macrophage
Activation
IL-1b IL-6
TNF-
TNF- IFN-g
Myeloid dendritic cell IFN-
TNF-
Innate immunity
Innate immunity
Adaptive immunity
Adapted from: Nestle FO, et al. N Engl J Med. 2009;361(5):496–509.
• Monocyte and neutrophil recruitment • Neovascularisation • Vasodilation • T cell influx • Keratinocyte hyperplasia
Outline
1. T cell subsets in humans
2. Psoriasis: a Th17-mediated disease through
production of TNF- and IL-17
3. IL-17 and IL-17 targeting
4. Th17 and Th17 targeting
5. T cell plasticity
DC-T cell-keratinocyte interactions drive the disease process and maintenance
Th1
Th17
IL-23
IL-12 TNF- IFN-g
IL-17A IL-17F IL-21 IL-22
TNF-
Keratinocyte
Keratinocyte
NK T cell
Plasmacytoid dendritic cell
Macrophage
Activation
IL-1b IL-6
TNF-
TNF- IFN-g
Myeloid dendritic cell IFN-
TNF-
Innate immunity
Innate immunity
Adaptive immunity
Adapted from: Nestle FO, et al. N Engl J Med. 2009;361(5):496–509.
• Monocyte and neutrophil recruitment • Neovascularisation • Vasodilation • T cell influx • Keratinocyte hyperplasia
Antimicrobial peptides
IL-1b
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
IL-17C Anti-p40 mAbs: ustekinumab Anti-p19 mAbs: SCH 900222 (also MK-3222) and LY2525623
Anti-p40 mAbs: ustekinumab
Normal activity of IL-12 and IL-23
Torti DC, Feldman SR. J Am Acad Dermatol. 2007;57(6):1059–68. Trinchieri G. Nat Rev Immunol. 2003;3(2):133–46.
NK or T cell membrane
Signal
IL-12 IL-23 p40
p40
p35 p19
Nestle FO, Conrad C. J Invest Dermatol. 2004;123(6):xiv-xv.
NK or T cell membrane
ustekinumab
ustekinumab
No signal
IL-12 and IL-23 neutralization
IL-12 IL-23
Effect of blocking IL-12 and IL-23 in psoriasis using anti-p40 antibody (ustekinumab)
Baseline Week 12
Images courtesy of PHOENIX 2 Investigators.
Outline
1. T cell subsets in humans
2. Psoriasis: a Th17-mediated disease through
production of TNF- and IL-17
3. IL-17 and IL-17 targeting
4. Th17 and Th17 targeting
5. T cell plasticity
T cell plasticity Can Treg cells convert to IL-17 effector cells ?
CD4
FoxP3
IL-17A
Bovenschen HJ et al. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest dermatol, 2011, 131:1853-1860
Key messages
• Psoriasis is a genetically based, auto-inflammatory disease
• Dendritic cells, T cells (Th1/Th17) and keratinocytes cross-talk to induce and maintain the disease
• DC produce IL-23 which activates Th17 cells leading to the production of IL-17 cytokines
• IL-17 activates keratinocytes which amplify the inflammatory response and initiate the vicious inflammatory circle. TNFa acts as a synergic cytokine
• Targeting Th17 and/or IL-17 results in dramatic improvement of psoriasis