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Jacques DUTRIEUX PhD . Modified IFN- a subtypes production and chemokine networks in the thymus during acute SIV infection, impact on thymopoiesis. DUTRIEUX J. et al. , AIDS Published online march 7th 2014. Institut Cochin INSERM U1016

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Jacques DUTRIEUX PhD.

Modified IFN-a subtypes production and chemokine networks in the thymus during acute SIV infection, impact on thymopoiesis

DUTRIEUX J. et al., AIDS

Published online march 7th 2014

Institut Cochin INSERM U1016

Team « Cytokines and viral infections »Rémi CHEYNIER


HIV infection impacts on thymopoiesis

Intra-thymicproliferation

From Dion et al. 2004

  • Thymopoiesis israpidlyaffectedduringprimary HIV infection (Hatzakiset al. 2000; Richardson et al. 2000; Douek et al. 2001; Dion et al. 2004)

  • Diminished thymocyte proliferation(Dion et al., 2004)

  • Consequence of IFN-aresponse ?

2


Acute HIV/SIV infection

Human

Rhesus macaque

VL

IFN-a

From Stacey et al. 2009

109

60

108

50

  • In both humans and macaques :Plasma IFN-a peaks around day 10 post-infection(Stacey et al., 2009; Khatissianet al. 1996; Giavedoniet al. 2000; Abel et al.2002; Bruelet al., 2014, Dutrieux et al. 2014).

107

106

40

105

IFNa (pg/ml)

30

Viral RNA load (copies/ml)

104

103

20

3

102

10

101

100

0

0

4

8

12

16

20

24

28

Days post-infection


Acute SIV infection study

SIVmac251 Infection (50AID50)IV

Necropsy D0 (3) and in acute phase(D3, D7, D10, D14)

24 rhesus macaques

Thymus sampling

Blood samplingD0, D3, D5, D7, D10, D12, D14

Plasma IFN-a measurement

IFN-a and chemokines mRNA quantifications and identification

T-cell subsets analysis

Thymic function analysis

4


Thymic modification in vivo

103

102

Intra-thymic proliferation

101

100

*

0

3

7/10

14

17

21

*

Days post-infection

70

60

50

40

30

Plasma IFN-a

p=0.017

r= -0.67

20

10

  • Intra-thymic proliferation decreased at day 10 post-infection

  • Diminished intra-thymicproliferation correlates with

  • plasma IFN-a concentration

0

-10

-6

-4

-2

0

2

Intra-thymic proliferation

(Fold change)

5


Interferon a diversity

13 IFNa

FromWoelket al. 2007

6


8

7

6

5

4

3

2

1

0

0

3

7

10

14

Days post-infection

103

102

101

100

10-1

Thymic production of IFN-a subtypes

Day 3

IFN-a1

IFN-a1

Day 14

Day 0

IFN-a12-15

IFN-a12-15

IFN-a2

IFN-a2

IFN-a14

IFN-a14

IFN-a3

IFN-a3

Number of expressed

IFN-a subtypes

IFN-a13

IFN-a4-6

IFN-a13

IFN-a4-6

IFN-a5

IFN-a5

IFN-a9

IFN-a9

IFN-a7

IFN-a7

IFN-a8

IFN-a8

IFN-a1

IFN-a12-15

IFN-a2

IFNa mRNA copies / 103 HPRT mRNA copies

IFN-a14

IFN-a3

IFN-a13

IFN-a4-6

**

IFN-a5

IFN-a9

IFN-a7

IFN-a8

Diversified thymic IFN-a expression

7


In vitro differentiation of simian thymocytes

Simian IFN-asubtypes

transfected in CHO

Healthy macaque thymus

Acidic purification

R-sIL-7

12 simian IFN-a

Flt3L

DN thymocytes

OP9-hDL1

14 days

Frequency of mature cells

Thymocyteproliferation

8


IFN-a subtypes differentially inhibit thymopoiesis

100

Day 5

Day 9

80

Day 12

60

*

Divided cells (%)

*

*

40

*

*

*

*

*

*

20

#

0

IFN-a7

IFN-a1

IFN-a2

IFN-a3

IFN-a4

IFN-a5

IFN-a6

IFN-a8

IFN-a9

Medium

IFN-a13

IFN-a14

IFN-a12/15

IFN-a subtypes differentially inhibit thymocytes proliferation without affecting their differentiation capability

9


IFN-a subtypes differentially inhibit thymopoiesis

*

*

*

100

Day 5

*

*

Day 9

80

*

Day 12

*

*

*

60

Divided cells (%)

40

20

#

0

IFN-a7

IFN-a1

IFN-a2

IFN-a3

IFN-a4

IFN-a5

IFN-a6

IFN-a8

IFN-a9

Medium

IFN-a13

IFN-a14

IFN-a12/15

In vivo-produced IFN-a subtypes demonstrate

major anti-proliferative effect

10


Chemokine-driven thymocyte migrations

CXCL12

CCL25

CCL19

CCL19

11


CCL25 transcription in the thymus

104

*

*

103

CCL25 mRNA copies/ 102 HPRT mRNA copies

102

101

C

100

0

3

7

10

14

Days post-infection

M

C

C

200µm

CCL25mRNA

DR

  • Cortical expression

  • Increased transcription by day 3

12


CCL19 transcription in the thymus

104

*

*

103

M

CCL19 mRNA copies/ 102 HPRT mRNA copies

102

C

C

101

CCL19mRNA

200µm

200µm

DR

100

0

3

7

10

14

Days post-infection

  • Medullar expression

  • Increased transcription by day 3

13


CXCL12 transcription in the thymus

CXCL12

DR

  • Expressed in subcapsular region

  • Decreased transcription by day 3

105

C

C

104

*

C

103

M

CXCL12 mRNA copies/ 102 HPRT mRNA copies

C

102

14

C

101

200µm

100

0

3

7

10

14

Days post-infection


In the thymus

Proliferation

CXCL12

  • Diversified IFN-a production

  • Thymic IFN-a subtypes Inhibit thymocytes proliferation

  • Modified thymic chemokine network

CCL25

CCL19

CCL19

15


In the thymus

  • Accelerated thymopoiesis

  • Increased thymic function

  • Increased naive T-cell diversity

Proliferation

CXCL12

  • Diversified IFN-a production

  • Thymic IFN-a subtypes Inhibit thymocytes proliferation

  • Modified thymic chemokine network

CCL25

Eventually lead to the characteristic

HIV-associated thymic exhaustion

CCL19

CCL19

16


Acknowledgements

Team Antigen presentation by dendritic cells

Agnès LEBON

Facilities

Team Cytokines & Viral Infections

Rémi CHEYNIER

Véronique FABRE-MERSSEMAN

Bénédicte DE MUYLDER

Suzanne MORGADO

Anne COUEDEL COURTEILLE

Isabelle BOURGAULT-VILADA

Magali RANCEZ

Stéphanie BEQ

Sandra ROZLAN

Rosalie PONTE

Vélislava TERZIEVA

Amandine BERNARD

Sandrine LOGEROT

Raphaëlle PARKER

Primate center Institut Pasteur

Céline GOMMET

Xavier MONTAGUTELLI


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