sous populations lymphocytaires t cd4+ et cd8+ de type 1...

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


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


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


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


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


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


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


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







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







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







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

sous populations lymphocytaires t cd4+ et cd8+ de type 1...

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