International Association of Biomedical Gerontology

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• International Association of Biomedical
  Gerontology
• 10th Congress
• Queens College/Cambridge
• September 2003
• T cell Replicative senescence
• pleiotropic effects on human aging
• Rita B. Effros
• Dept of Pathology Laboratory Medicine
• David Geffen School of Medicine at UCLA

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Viral infections and aging

• increased incidence and severity (influenza, RSV,
  HIV, SARS)
• re-emergence of latent infections

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Cytotoxic ( CD8) T cells
gt 1018 different antigen receptors
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Replicative senescence
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(No Transcript)
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Reduced apoptosis
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Effect of repeated stimulation on telomerase
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Effect of repeated stimulation on telomerase

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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 ? with ageBoucher et al.,
Exp. Gerontol. 33267, 1998

• in CD4 in CD8
• Neonates NT NT
• Young adult (20-40) 4 42
• Elderly (70-90) 12 79

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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 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 BONE RESORPTION Role of T cells
REGULATION OF OC FORMATION AND FUNCTION Model
T CELLS
MONOCYTES
Stimulatory Factors
RANKL
TNFa
IL-1 TNFa
Inhibitory Factors
TNFa
ACTIVE OC
OC PRECURSORS
Differentiation and activation
OPG
M-CSF
RANKL
RANKL
TGFb
IL-6 PGE2 GM-CSF
TGFb
STROMAL CELLS
(Modified from SAGE KE/ B.L. Riggs)
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Effect of culture age onproduction of TNF alpha
TNFa pg/ml
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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
RANKL ng/ml
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Ectopic telomerase expression leads to lifespan
extension of virus-specific CD8 T cells
Telomere length stablization, prevents
accumulation of p16, p21
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Correction of senescence-associated cytotoxic
defect
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Replicative 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 Support UCLA Xiao
ming Zhu Hector 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)