Impact of regulatory T cells on immune responses to SIV

SIVmac251

Macaques with few T-regs

Macaques with many T-regs

Follow T cell responses,

activation, and disease outcome

Chronic immune activation and HIV disease progression

• Among untreated patients, T cell activation is strongly associated with clinical progression to AIDS

• On therapy, T cell activation is associated with decreased CD4+ T cell gains

• Mechanisms that may underly these associations:– Depletion of the naïve T cell pool– Proliferation and loss of effector-memory T cells– Interference with T cell production in bone marrow and

thymus– Increased replication of virus within T cells

Immune control of SIV

• Appearance of SIV-specific CD8+ T cells is

coincident with decline of viral load from peak

• CD8-depleted macaques do not reduce viral

load relative to peak

• Specific MHC-I alleles are associated with

slow disease progression

Impact of regulatory T cells on immune responses to SIV

SIVmac251

Adult macaques with 4% T-regs

Infant macaques with 8% T-regs

Follow T cell responses,

activation, and disease outcome

Hypothesis: In the setting of SIV infection, regulatory T cells will control immune activation

and thereby slow disease progression

CD25 CD25

Infant macaque T-regs are CD25+CD127lowC

D12

7

FO

XP

3

Add CD25 1:3

CFSE

CD25-depletedAll cells Add CD25 1:3CD25-depletedAll cells

Infant macaque T-regs are CD25+CD127low

Infant macaques have more T-regs in peripheral blood

0

2

4

6

8

10

****

CD

25+

CD

127l

ow,

% o

f CD

3+C

D4+

1 wk

3 wks

5 wks

18-3

0 m

os

4-5

yrs

Infant macaques have more T-regs in peripheral blood

0

2

4

6

8

10

12

14

****

0

2

4

6

8

10

12

14 ****

0

2

4

6

8

10

12

14

*****

0

50

100

150

200

250

300

350

****

% C

D25

+%

CD

25+

FO

XP

3+

% C

D25

+C

D12

7low

% C

D25

+ p

er µ

L

Infant macaques have more T-regs in lymph node tissue

0

1

2

3

4

5

6

7

8**

**

Node

FO

XP

3+,

% o

f C

D4+

Adult

Infant

Infant macaque T-regs are more highly suppressive in vitro

Uninfected

0

20

40

60

80

100

Div

isio

n in

dex,

% o

f C

onro

l

Adult

Infant

*p < 0.0001

Infected

0

25

50

75

100

Div

isio

n in

dex,

% o

f C

onro

l1:3 T-regs:RespondersT-regs:Responders

Impact of regulatory T cells on immune responses to SIV

SIVmac251

Adult macaques with 4% T-regs

Infant macaques with 8% T-regs

Follow T cell responses,

activation, and disease outcome

Disease progression in adult and infant macaques

0 5 10 15 20

0

4

5

6

7

8

32

Adult

Infant

log 1

0(vR

NA

)

Weeks post-infection

0.0

0.5

1.0

1.5

2.0

2.5

Infant

0.0

0.5

1.0

1.5

2.0

2.5

DC

CD8+ T cell responses to SIV

IFN

-+

TN

F-

+, %

of

CD

8

IFN

-+

TN

F-

+, %

of

CD

8

Adult

Infant

Adult—all cells

Infant—CD25-depleted

Adult—CD25-depletedInfant—all cells

SIV-specific CD4+ T cell proliferation is suppressed by T-regs

0 4 8 12 160.0

0.2

0.4

0.6

0.8

1.0

1.2

Adult

Infant

CF

SE

dim

, % o

f CD

4+

0 4 8 12 160.0

0.5

1.0

1.5

CF

SE

dim

, % o

f CD

4+

Adult—all cells

Infant—CD25-depleted

Adult—CD25-depleted

Infant—all cells

0 4 8 12 160.0

0.5

1.0

1.5

2.0

0 4 8 12 160.0

0.2

0.4

0.6

0.8

1.0

1.2

SIV-specific CD4+ T cells are suppressed by T-regs

IFN

-+

IL-2

+, %

of

CD

4

IFN

-+

IL-2

+, %

of

CD

4

Infant

Adult

Infant

Adult—all cells

Infant—CD25-depleted

Adult—CD25-depletedInfant—all cells

0 1 2 4 6 8 160

10

20

30

40

50

Widespread T cell activation is not suppressed by infant macaque T-regs

Infant CD4

Adult CD8

Infant CD8

Adult CD4

Conclusions

• Infant macaques have more regulatory T cells in peripheral blood and tissues

• Infant T-regs are more highly functional in vitro

• After infection with SIV, most infants had high viral loads and rapid disease progression

• Infected infants displayed weak and transient SIV-specific T cell responses

Conclusions

• T-regs in the infant but not the adult directly suppressed SIV-specific CD4 responses

• In infants and adults, T-regs were not able to directly suppress SIV-specific CD8 responses

• In infants and adults, T-regs had no apparent effect on T cell activation

• These observations suggest that the T-reg compartment of the infant macaque facilitates rapid disease progression

Acknowledgements

• Paul Baum

• David Favre

• Juliet Easlick

• Joseph Moore

Abel LaboratoryMcCune Laboratory

• Marta Marthas

• Koen van Rompay

UC Davis