international association of biomedical gerontology 10 th congress queens college/cambridge...

International Association of Biomedical Gerontology

10th CongressQueens College/Cambridge

September 2003

T cell Replicative senescence:pleiotropic effects on human aging

Rita B. Effros

Dept of Pathology & Laboratory MedicineDavid Geffen School of Medicine at UCLA

Viral infections and Viral infections and agingaging

increased incidence and severity (influenza, RSV, HIV, SARS)

re-emergence of latent infections

Cytotoxic ( CD8) T cells Cytotoxic ( CD8) T cells

> 1018 different antigen receptors

Replicative senescence

Reduced apoptosis

Effect of repeated stimulation on Effect of repeated stimulation on telomerasetelomerase

Effect of repeated stimulation on Effect of repeated stimulation on telomerasetelomerase

*

X

Immunobiology: The Immune System in Health & Disease,

3rd edition, by Janeway & Travers ( Current Biology Limited & Garland Publishing)

CD28-negative T cells CD28-negative T cells with with ageage

Boucher et al., Exp. Gerontol. 33:267, 1998Boucher et al., Exp. Gerontol. 33:267, 1998 in CD4 in CD8

Neonates NT NT

Young adult (20-40) 4% 42%

Elderly (70-90) 12% 79%

*

A

Mea

n T

RF

Len

gth

(kb

)

5

6

7

8

9B C

SN SP CEN CD28+

CD28-

CD28- PBMC

CD28+

CD28-

A

Mea

n T

RF

Len

gth

(kb

)

5

6

7

8

9B C

SN SP CEN CD28+

CD28-

CD28- PBMC

CD28+

CD28-

CD28- T cells have shortened telomeres

unable to proliferate

resistant to apoptosis

Do senescent CD8 T cells affect other cell types and organ

systems in vivo ?

CD8+ CD28- T cellsCD8+ CD28- T cells

correlate with poor response to flu vaccine

suppress helper T cells

disease progression in ankylosing spondilitis

organ transplant patients-may suppress T cells that would reject the graft

correlate with osteoporotic fractures

REGULATION OF OC FORMATION AND FUNCTIONModel

REGULATION OF BONE RESORPTIONRole of T cells

T CELLSMONOCYTES

ACTIVE OC

STROMAL CELLS

TGF

TNF

IL-6PGE2

GM-CSF

M-CSF

OC PRECURSORS

TNF

TGF

Differentiationand activation

Stimulatory Factors

Inhibitory Factors

RANKLRANKL

OPG

IL-1TNF

RANKL

(Modified from SAGE KE/ B.L. Riggs)

Effect of culture “age” onEffect of culture “age” onproduction of TNF alphaproduction of TNF alpha

0

10

20

30

40

50

60

70

80

TN

F

pg

/ml

25164

Population Doublings

Production of “RANKL” by activated T cells

(Receptor Activator for NFkB Ligand)

Production of RANKL by activated T cells

0

1

2

3

4

5

control IL-2 PHA PHA + IL-2 IL-7

RA

NK

L n

g/m

l

Ectopic telomerase expression leads to lifespan extension of virus-specific CD8 T cells

0

10

20

30

40

50

60

70

80

0 200 400 600 800 1000 1200

Days in culture

Po

pu

lati

on

Do

ub

lin

gs

(PD

)

hTERT

vector

Telomere length stablization, prevents accumulation of p16, p21

Correction of senescence-Correction of senescence-associated cytotoxic defectassociated cytotoxic defect

8765432100

20

40

60

80

100

Passage

% S

pe

cific

Lys

is

Untransduced CTL (Control)Empty Vector-Transduced CTL (Control)hTERT-Transduced CTL

FIGURE 4

Replicative senescenceReplicative senescence

end stage of normal T cell differentiation increased proportions in elderly reduced anti-viral function once generated, senescent CD8 T cells persist

? exert broad physiological effects hTERT corrects only some of the defects

associated with CD8 T cell senescence (CD28, compounds that telomerase) Reversal of T cell replicative senescence can

improve both immune function and bone status

Collaborators and SupportUCLA

Xiaoming ZhuHector Valenzuela Otto Yang Mirabelle Dagarag Janis Giorgi Lucia Graham Roger Detels Tankdik Evazyan Farhad Parhami

Geron Corporation Calvin Harley, Choy-Pik Chiu

(UC BioSTAR, NIH ,Plott Endowment, UCLA Center on Aging)