international association of biomedical gerontology 10 th congress queens college/cambridge...
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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
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Viral infections and Viral infections and agingaging
increased incidence and severity (influenza, RSV, HIV, SARS)
re-emergence of latent infections
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Cytotoxic ( CD8) T cells Cytotoxic ( CD8) T cells
> 1018 different antigen receptors
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Replicative senescence
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Reduced apoptosis
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Effect of repeated stimulation on Effect of repeated stimulation on telomerasetelomerase
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Effect of repeated stimulation on Effect of repeated stimulation on telomerasetelomerase
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X
Immunobiology: The Immune System in Health & Disease,
3rd edition, by Janeway & Travers ( Current Biology Limited & Garland Publishing)
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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%
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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
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Do senescent CD8 T cells affect other cell types and organ
systems in vivo ?
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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
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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)
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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
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Production of “RANKL” by activated T cells
(Receptor Activator for NFkB Ligand)
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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
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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
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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
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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
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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)