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
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)