Memory results from a change in frequency and properties

1
Cellular basis of immunological memory

• Memory results from a change in frequency and
  properties
• of antigen-specific lymphocytes that persists
  after antigen
• is eliminated.
• Memory has two properties carried out by
  different cells
• Secondary responses
• Immediate protection

Memory B cells Central memory T
Plasma cells and antibodies Effector memory T

• How are memory cells generated?
• How are they maintained for our lifetime?

2
Figure 1-20
3
From primary responses to long term memory
(numbers)
Expansion
Contraction
Steady state
4
(No Transcript)
5
Two subsets of memory T cells
Th1
monocytes
CCR5 CXCR3
Naïve T cells
IFN-g
CCR7
IL-2
Effector memory T cells
Eotaxin MDC
basophils
Th2
CCR3 CCR4 CCR8 CRTh2
IL-4 IL-5
eosinophils
IL-2
CCR7 CD62L
Central memory T cells
6
Two subsets of memory T cells
Th1
monocytes
CCR5 CXCR3
Naïve T cells
IFN-g
CCR7
IL-2
Effector memory T cells
Eotaxin MDC
basophils
Th2
CCR3 CCR4 CCR8 CRTh2
IL-4 IL-5
eosinophils
IL-2
Maintenance of cytokine memory ? Commitment or
flexibility ?
CCR7 CD62L
Central memory T cells
Uncommitted precursors?
7
Division of labor among memory T cells
secondary lymphoid organs
peripheral tissues
Ag-DC
Ag-DC
Naïve T
Central memory T
Effector memory T
Home to lymph nodes DC and B cell help Precursors
of effectors
Home to non-lymphoid tissues Immediate effector
function (cytokines, cytotoxicity)
Secondary responses Protective memory
Immediate protection Reactive memory
8
Migratory properties of subsets of human CD4/CD8
T cells
9
Homeostasis of memory T cells
secondary lymphoid organs
peripheral tissues
cytokines
Naïve T
Central memory T
Effector memory T
persisting antigen
Geginat et al. J. Exp. Med. 2001
10
From primary responses to long term memory
(quality)
signal strength
dead
Homogenous stimulation
Fit CCR7- Effector
Fit CCR7 Non effector
Unfit IL-15R- BCLXL-
Survival of the fittest?
Central memory
Effector memory
Sallusto et al, Nature 1999
11
Antigen-independent mintenance of B- and T-cell
memory
12
(No Transcript)
13
(No Transcript)
14
Naïve B
Long lived plasma cells in bone marrow half life
3 months (Radbruch, 1997 Ahmed, 1998)
b
a
c
TT
p
s
z
u
q
g
o
w
m
Memory B
TT
p
s
z
u
q
g
o
w
m
Serum Ig

• Plasma cells do not divide. How can they be
  replenished?
• Persisting antigen driving memory B cells
  (Gray, 1990 Zinkernagel, 1995)
• Polyclonal activation of all memory B cells in
  the absence of antigen

15
Human memory B cells are poised to proliferate
and differentiate in response polyclonal stimuli.
Does this mechanism maintain serological memory?
16
Peripheral blood
Bone marrow plasma cells
Naïve B
a
a
b
Ag-a
a
a
a
c
x
p
s
x
x
z
u
q
g
x
x
o
w
m
Ag-x
x
p
s
All specificities
z
u
q
g
Serum Ig
o
w
m
Continuous polyclonal activation of all memory B
cells in the absence of antigen
17
First prediction Under steady state conditions
plasma cells specific for recall antigens should
be present at low levels in peripheral blood
Anti-TT IgG secreting cell 10 years after TT boost
18
First prediction Under steady state conditions
plasma cells specific for recall antigens should
be present at low levels in peripheral
blood Their frequency should be comparable to
that found in polyclonally activated memory B
cells
CpG IL-2
Day 6 cultures of memory B (CpGIL-2)
Peripheral blood
A) 1 in 1800 1 in 1300 B) 1 in 12000 C) 1
in 10000
1 in 950 1 in 500 1 in 6000 1 in 3500
Anti-Tetanus Toxoid / IgG secreting cells
Donor A was tested 10 years after boost
19
Second prediction Under steady state
conditions serum antibody titers should correlate
with the frequency of memory B cells responsive
to polyclonal stimuli
20
Naïve B
Third prediction Boosting with any Ag should
lead to an increase of circulating plasma cells
of all memory specificites due to increased
availability of help
Bone marrow plasma cells
b
a
c
x
p
s
TT
TT
TT
TT
TT
z
u
q
g
TT
TT
TT
TT
TT
TT
Memory B
o
w
m
TT
Turnover
TT
p
s
x
p
s
z
u
q
g
z
u
q
g
o
w
m
Serum Ig
o
w
m
Boosting with TT
ELISPOTS IgG Anti-TT Anti-T Gondii Anti-measles
Plasma cells / 106 PBMC
Days after boost
21
Conclusions

• Short term memory (Antigen-dependent and last
  less than one year)transient production of short
  lived (and long lived) plasma cells.
• Long term memory (Antigen-independent and is
  life long)polyclonal activation of all memory B
  cells through bystander help, CpGThis mechanism
  preserves all the specificities generated during
  the antigen-driven response.

22
Antigen-independent mintenance of B- and T-cell
memory