NaiveTcell dynamics of mice and men

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NaiveT-cell dynamics of mice and men

• José Borghans

The best-laid schemes o' mice an' men, Gang aft
agley The most carefully prepared plans may go
wrong
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From mice to men...(How) can we extrapolate?
Effect of thymic involution during
aging? Contribution of thymic output versus
peripheral proliferation?
2 years
mice
80 years
men
How to scale?
2 years
mice
80 years
men
Young young?
3
From mice to men...Separate dynamics of RTE?
Naive T-cell pool RTE resident naive RTE no
homeostasis for 3 weeks, after that short
half-life
(Berzins et al. 1999)
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Of mice... Naive T-cell dynamics using 2H2O
H-O-H
Label acquisition - proliferation - thymic
output Loss of label - cell death -
differentiation/migration
H-O-H
4w
2H2O
C57Bl/6
labeled
time
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Analysis of 2H2O data in miceThe model
whole population
recently produced cells only
Grossman et al. 1999
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Short lifespan of naive T cells in mice
Delay t T ?, where ? 7
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2H2O data do not support kinetically distinct
pool of RTE in mice
during label after stop label
Typically p lt d
In mice p d Naive T-cell pool in mice
kinetically homogeneous So far no evidence for
separate RTE dynamics
whole population
recently produced cells only
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Distinguishing between T-cell proliferation and
thymic output
Label acquisition - thymic output -
proliferation Loss of label - cell death -
differentiation/migration
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Naive T-cell dynamics after thymectomy
Naive CD4 (spleen)
Naive CD8 (spleen)
Control
Control
Cells (x106)
Tx
Tx
Bi-phasic loss of naive T cells due to rapid loss
of RTE?
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Thymic output in mice- Changes with age -
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Naive T-cell homeostasis
Thymus
Periphery naive CD4
Naive T cell numbers stay relatively constant,
while thymic output decreases
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Thymectomy data explained without RTE!
Naive CD4 (spleen)
Naive CD8 (spleen)
Control
Control
Tx
Tx
e 2.8 10-2 rn 3.0 10-3 dn 1.7
10-9
e 2.8 10-2 rn 2.0 10-3 dn 6.8
10-10
Naive CD8 better maintained than CD4 (longer
lifespan)
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Estimated lifespans using Tx or 2H2O very similar
12 week old Life-span naive CD4 35 days, CD8 95
days After Tx 68 days 105
days
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All data explained without naive T-cell
proliferation in mice
N e f(t) rnN dnN2
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CD4 SP CD8 SP
1
Contribution to spleen (cells 106 / day)
0.1
0.01
0.001
60
50
40
30
20
10
0
Time (weeks)
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No room for peripheral proliferation of naive T
cells in mice
Peripheral proliferation
Total Naïve T-cell production Naïve CD4 ? p
0.28 106 / day Naïve CD8 ? p 0.13 106 /day
Heavy water
Thymic output
Loss
Thymic output
Thymectomy
Loss
Thymic output CD4 thymic emigrants ? 0.35 106 /
day CD8 thymic emigrants ? 0.12 106 / day
Peripheral proliferation
Naive T-cell production is almost completely due
to thymic output!
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What is the maximum number of divisions naive
T-cells make in mice?
Thymus
Periphery naive CD4
Naive T cell numbers stay relatively constant,
while thymic output decreases
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Again, thymectomy data explained without RTE!
Naive CD4 (spleen)
Naive CD8 (spleen)
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Naive T cells in normal mice make hardly any
division in their life time
Live 43 days, divide every 300
Live 77 days, divide every 200
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And indeed... no TREC decline in mice
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Naive T-cell dynamics in mice hardly change with
age
Young mice12 weeks
Old mice 85 weeks
43 days
42 days
91 days
77 days
p d and young old The naive pool of a mouse
is a big homogeneous RTE pool
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Contrary to ... menTREC decline in healthy humans
Douek et al. Nature 1998
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Even in naive T-cell pool 100-fold TREC decline
in humans
Van den Dool De Boer JI 2006
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TREC decline is evidence for naive T-cell
homeostasis in humans
With homeostasis Without homeostasis
Dutilh De Boer 2003, Borghans De Boer Imm.
Rev. 2007
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TREC dilution suggests naive T-cell proliferation
in men
Or longer naive lifespan with age leading to more
rounds of proliferation
Increasing proliferation rate with age
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CD31 proposed as marker for non-divided naive CD4
T cells
Naive
Memory
thymus
CD31
CD31-
CD31 naive T cells have consistently higher TREC
content than CD31- Suggestion CD31 naive T
cells represent (non-divided) RTE CD31-
naive T cells have divided
Kimmig et al J. Exp Med 2002
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However, even CD31 naive T cells divide in
humans!
TREC content per cell
Age (in years)
See also Kilpatrick et al. 2008
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Less RTE than CD31 naive T cells
Naive
Memory
thymus
CD31
CD31-
Naive
Memory
CD31-
thymus
CD31
RTE
non-RTE
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Calculate maximum number of RTE
Naive
Memory
CD31-
thymus
CD31
RTE
non-RTE
A31 r ARTE (1 r) Anon ARTE ASP ACB
Anon gt 0 A31 gt r ARTE A31
ARTE
Anon gt A31- A31 gt r ARTE (1 r) A31-
A31 A31- ARTE A31-
r lt
r lt
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Fraction (non-divided) RTE in naive T-cell pool
max 10 in adulthood
Based on CD31
Fraction RTE in naive pool
Based on TREC contents
Age (in years)
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How much naive T-cell production per day in
men?D2O in young healthy volunteers
Vrisekoop et al. PNAS 2008
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T-cell turnover in healthy individuals
Vrisekoop et al. PNAS 2008
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T-cell turnover in healthy individuals

• Expected lifespan of memory cells is 0.6 1.0
  years
• naive
  cells is 6.0 9.4 years
• 2. Newly produced naive T cells are
  preferentially incorporated in the peripheral
  pool Incompatible with significant pool of
  short-lived RTE

Vrisekoop et al. PNAS 2008
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Extrapolating from mice to men
Men
Naive CD4
live 6 years live 9.4 years At most 10 of
naive cells non-divided Recently produced cells
live longest

• live 5 6 weeks
• live 10-14 weeks
• Naive T cells hardly divide
• Naive T-cell pool homogeneous

Naive CD8
Proliferation
Proliferation
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Scaling from mice to men...
2 years
mice
80 years
men
Mice live 80 weeks naive CD4 T cells 6 weeks,
CD8 11 weeks Humans live 80 years naive CD4 T
cells 6 years, CD8 10 years
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Acknowledgements
Theoretical Biology, Utrecht University
Immunology, UMCU Bregje de Boer Elise
Schrijver Gerrit Spierenburg Mette Hazenberg
Endocrinology Metabolism AMC An Ruiter Mariëtte
Ackermans Saskia van der Crabben Hans Sauerwein

Vitaly Ganusov Becca Asquith Derek Macallan