Generation and maintenance of human memory cells during viral infection.

[Mingus]

I'm very sorry for the format but it would be easyer to check for the complete article in PDF format.
Anyway the text is here if you want to copy some part of it.

What do influence the immune memory ? they talk about that.

______________________

Generation and maintenance of human memory cells during viral infection.-PDF complete article.



Page 1
248
Typical immune responses lead to the prominent clonal
expansion of antigen-specific T cells followed by their
differentiation into effector cells. Most effector cells die at the
end of the immune response but some of the responding cells
survive and form long-lived memory cells. The factors
controlling the formation and survival of memory T cells are
discussed. Recent evidence suggests that T memory cells
arise from a subset of effector cells. The longevity of T memory
cells may require continuous contact with cytokines, notably
IL-15 for CD8
+
cells.
Addresses
Department of Immunology, IMM4, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Correspondence: Jonathan Sprent; e-mail: jsprent@scripps.edu
Current Opinion in Immunology 2001, 13:248?254
0952-7915/01/$ ? see front matter
? 2001 Elsevier Science Ltd. All rights reserved.
Abbreviations
APC
antigen-presenting cell
FasL
Fas ligand
IFN-I
type I interferons
IL-2R
IL-2-receptor
PLAP
placental alkaline phosphatase
Introduction
A hallmark of the immune system is that secondary
responses to infectious agents are generally much more
vigorous than primary responses. Generation of immuno-
logical memory following contact with pathogens is
antigen-specific and reflects a combination of humoral
(?antibody?) and cellular immunity, which is often life-
long [1?10].
Humoral immunity is especially important and is due in
part to generation of memory at the level of B cells. Thus,
after initial contact with antigen, some of the B cells par-
ticipating in the primary response form memory cells;
generation of these cells is the end result of clonal expan-
sion, differentiation and affinity maturation. These
?primed? B cells are more efficient than na?ve B cells and
give heightened humoral responses on secondary contact
with the antigen concerned. Despite the importance of
B cell memory, it has recently become apparent that
humoral immunity can also reflect the long-term survival
of plasma cells (antibody-forming effector B cells) generat-
ed during the primary response [11,12]. These cells lodge
in the bone marrow and continuously secrete antibody into
the bloodstream, probably for many years.
Immunological memory is also apparent at the level of
T cells ? the carriers of cellular immunity. As for B cells,
a proportion of na?ve T cells differentiate into long-lived
memory T cells at the end of the primary response [1?10].
Reflecting their primed status, memory T cells produce
vigorous secondary responses to antigen and rapidly elimi-
nate pathogens by destroying infected cells (cytolysis by
CD8
+
T cells) and also by controlling B cell responses
(?help? by CD4
+
cells). Here we review recent advances in
our understanding of the factors controlling the formation
and survival of memory T cells.
Generation of memory T cells
To eliminate pathogens, primary immune responses have
to be as intense as possible. Pathogens replicate rapidly
and, to keep pace, antigen-specific T cells divide at a
prodigious rate (as often as every six hours) and generate
enormous numbers of effector cells [9,13?16]. These cells
usually eliminate the pathogen, thus terminating the
response. Effector cells are then redundant and most of
these cells are destroyed en masse, presumably to provide
?space? for the subsequent responses of na?ve T cells.
Destruction of effector cells at the end of the primary
response is a rapid and highly efficient process. Precisely
how the cells are destroyed is not fully understood but is
thought to be initiated by loss of contact with antigen:
TCR stimulation ceases and leads to a decline in the pro-
duction of life-sustaining cytokines. Deprived of these
stimuli, T cells activate various intracellular death path-
ways and rapidly succumb to apoptosis [17,18]. Activation
of these death pathways reflects exchange of the intracel-
lular proteins that dock with certain cell-surface molecules,
notably Fas. Thus, dissociation of FLIP from Fas converts
Fas to a death-inducing molecule, with the result that lig-
ation of Fas by the Fas ligand (FasL) triggers activation of
cytolytic effector molecules (caspases) [19?22].
A priori, one might expect considerable redundancy in the
mechanisms leading to death of effector cells. Surprisingly,
this is not the case because many different molecules in or
on T cells seem to be indispensable for eliminating effector
T cells. Thus, gene knockout mice lacking such diverse
molecules as IL-2 [23], IL-2-receptor (IL-2R)α [24?26], IL-
2Rβ [27,28], Fas [18,29], FasL [18,29], CTLA-4 [30], PD-1
[31] or TGF-β [32] develop prominent hypertrophy of the
secondary lymphoid organs as the result of unrestrained T
cell proliferation/survival. The implication, therefore, is that
the default pathway for effector cells is survival rather than
death. As discussed below, this point has important implica-
tions for the generation of memory cells.
Given that more than 90% of T cells participating in the
primary response are rapidly destroyed, how do a small
proportion of these cells survive to become long-lived
memory cells? This question has been posed repeatedly
over the past 50 years but is still largely unresolved. It is
often tacitly assumed that generation of memory is an
Generation and maintenance of memory T cells
Jonathan Sprent and Charles D Surh
Page 2
Generation and maintenance of memory T cells Sprent and Surh 249
instructional process: most T cells are doomed to die at the
end of the primary response, and memory cells arise from
a small subset of cells that have somehow learned to avoid
death. However, given the conspicuous escape from death
by effector cells in various gene knockout mice (see
above), one can make the opposite argument, namely that
memory cell generation is not an instructional but a default
pathway. In other words, the T cells generated in the pri-
mary response are not programmed to die but to survive.
An instructional process does operate, but it acts largely by
killing most of these cells and their precursors ? rather
than by teaching memory cells to survive ? thereby pre-
venting the immune system from being swamped by
memory cells.
In speculating on memory cell generation, it has to be
borne in mind that, at least for CD8
+
cells, the fine speci-
ficity of T memory cells is established and fixed at the end
of the primary response [33?36]. It is also clear that the fre-
quency of T memory cells specific for particular antigenic
epitopes correlates closely with the extent of proliferation
(clonal burst size) of the precursor cells during the primary
response [37]. In considering these points, a key issue is
whether memory T cells are the descendants of fully dif-
ferentiated effector cells or arise from partly differentiated
cells. This is a difficult issue to address experimentally
because there is no acknowledged definition of a ?fully dif-
ferentiated? T cell. Nevertheless, it is now well established
that long-term memory results when na?ve T cells are
induced to undergo several rounds of cell division in
response to antigen in vitro and are then adoptively trans-
ferred in vivo in the absence of antigen [38?44,45
?
]. It has
also been shown recently that memory CD8
+
cells can be
generated from activated T cells displaying known effector
function, that is, from an in vitro expanded population in
which virtually all of the activated cells express perforin
[46
?
]. Likewise, memory cells can arise from T cells that
synthesize IL-2 [47
?
].
Further evidence that memory cells are the direct
descendants of effector cells came from an elegant genet-
ic recombination system in which Granzyme-B synthesis
by activated CD8
+
cells was marked by expression of a
reporter gene, human placental alkaline phosphatase
(PLAP) [48
?
]. The unexpected finding in this study was
that PLAP
+
cells accounted for only a small proportion
(10%) of CD8
+
cells at the height of the primary response
but were a dominant population at the level of memory
T cells. The implication, therefore, is that memory cells
are selected from a unique subset of effector cells rather
than from effector cells in general. As Jacob and
Baltimore [48
?
] pointed out, however, it is mysterious
that many of the effector cells (cytolytic cells) generated
in the primary response were PLAP
?
. It is also odd that,
in unimmunized mice, PLAP expression was not detect-
ed in normal ?memory-phenotype? (CD44
hi
) cells, that is,
in T cells that are presumed to carry memory for various
environmental antigens.
Although clearly informative, the above studies do not defi-
nitely resolve the issue of whether memory cells arise from
fully differentiated effectors. On this point, it is notable that
memory fails to occur when T cells undergo ?exhaustive?
proliferation to high doses of viruses [49]; in this situation,
effector T cells are generated in enormous numbers but
then die en masse, presumably because the cells are all dri-
ven to a terminal stage of differentiation where escape from
?activation-induced cell death? (AICD) is irreversible.
Accordingly, memory cells may normally arise from a subset
of cells that express a full range of effector functions but,
perhaps because of lack of prolonged contact with antigen,
have yet to be pushed hard enough to initiate AICD. Hence
memory cells might be drawn from a population of straggler
cells that only arrive at the site of infection during the later
stages of the immune response [3].
The capacity of some effector cells to evade death and sur-
vive as memory cells is presumably determined by the
particular conditions encountered during antigen-present-
ing cell (APC)/T cell interaction. Many costimulatory
molecules on APCs, including B7, 4IBBL and OX40L,
play an important role in T cell priming, and blocking
T cell interaction with these ligands reduces clonal burst
size and memory cell generation in parallel [7]. However,
other molecules on APCs, notably CD40, seem to be cru-
cial for promoting T cell survival. Thus, in the absence of
CD40L−CD40 interaction, clonal expansion of CD8
+
cells
is near normal but is followed by enhanced cell death and
only limited generation of memory cells [7].
How APC molecules such as CD40 protect effector cells
from death is still unclear. Either directly or indirectly,
these molecules may function by inducing upregulation of
anti-apoptotic molecules in T cells, for example Bcl-2 [50],
Bcl-X
L
[39] and lung Kruppel-like factor (LKLF) [51], and
perhaps also by stimulating T cells to express additional
costimulatory molecules, for example ICOS [52], or by
causing T cells to synthesize calcium/calmodulin kinase
[53] or initiate changes in surface O-glycans [54]. In addi-
tion, APCs may prevent T cell death by secreting
protective cytokines such as type I interferons (IFN-I)
[55], IL-15 [56] or IL-7 [57].
Subsets of memory T cells
In terms of their surface markers and functions, CD4
+
and
CD8
+
memory cells show considerable heterogeneity.
With regard to function, memory cells differ generally from
na?ve cells in being hyper-responsive to antigen and in syn-
thesizing cytokines in large quantities [38?44,45
?
,58].
Especially at the level of CD4
+
cells, memory cells tend to
synthesize several different cytokines, the particular
cytokines being determined by the conditions encoun-
tered during T cell priming. Most immune responses are
initiated in the T-cell-dependent areas of the lymphoid tis-
sues by dendritic cells [59]. Through local release of IL-12,
these professional APCs skew the precursors of memory
cells towards production of IFN-γ (Th1 memory cells).
Page 3
250 Lymphocyte development
Other memory cells, Th2 cells, produce different
cytokines, notably IL-4. The precise conditions required
for priming Th2 memory cells are unclear but a high local
concentration of IL-4 and TGF-β combined with low
IL-12 seem to be important. These conditions may arise
when the responding precursor T cells move away from
professional APCs and make contact with other APCs, for
example B cells [10]. Despite the existence of polarized
Th1 and Th2 cells, many memory cells are not polarized
and can display an apparently random selection of
cytokines upon re-stimulation [44,59?61]. Hence, for
cytokine production, memory cell generation may in part
be a stochastic process [61].
Memory T cells also fall into two broad categories on the
basis of their activation status [2,8,59,60,62?64,65
?
,66].
Typical memory cells are relatively quiescent and need to
be re-activated before expressing effector function.
Phenotypically, resting memory cells (also termed ?central?
memory cells [59]) can closely resemble na?ve cells, for
example, in expressing the lymph-node-homing receptors
CD62L [40,67] and CCR7 [65
?
]. Nevertheless, resting
memory cells differ generally from na?ve cells in express-
ing some of the characteristic markers of activated/effector
T cells, for example a CD44
hi
phenotype. In addition, rest-
ing memory cells have a faster background rate of
proliferation (turnover) in vivo than na?ve cells [68] and, as
mentioned above, display stronger effector function, for
example, cytokine production, on contact with specific
antigen. A second category of memory cells displays many
of the features of effector cells. These activated memory
cells lack CD62L and CCR7 lymph-node-homing recep-
tors and thus tend to be excluded from lymph nodes
[2,65
?
,69]. For CD8
+
cells with direct lytic activity, effector
memory cells are located largely in the spleen and are also
found in the gut mucosa [63].
The inter-relationship of resting and activated memory
T cells is unclear. The simplest possibility is that activated
memory cells represent a subset of cells that retain TCR
contact with small quantities of specific antigen left over
from the primary response [2,64]. This is a likely possibil-
ity in lymphocyte choriomeningitis virus infection of mice
because trace amounts of this virus can be detected long
after the primary response [70]. Other infections appear to
be completely eliminated by the immune system, howev-
er, and there is firm evidence that memory can persist in
the apparent total absence of specific antigen [37,71?74].
Alternatively, the presence of effector memory cells may
reflect intermittent activation of memory cells through
contact with cross-reactive environmental antigens [75] or
even self-antigens (see below).
There is continuing debate on the relative importance of
activated and resting memory cells. Some workers contend
that secondary responses to pathogens are not effective
unless the responding T cells are in a pre-activated state and
can express direct effector function [64]. The competing
argument is that the rate at which resting memory cells can
differentiate into activated effector cells is so rapid that the
need for pre-activated memory cells is minimal [76]. This
debate will undoubtedly continue.
Memory cells arising through homeostatic
proliferation of na?ve cells
From adoptive transfer experiments in mice, it has recent-
ly become apparent that reducing the total numbers of
T cells below a certain threshold causes residual na?ve cells
to proliferate. This proliferative response is directed large-
ly (reviewed in [6,77]), although not entirely [78,79], to
self-ligand that initially induced positive selection of the
T cells in the thymus. Such ?homeostatic? proliferation of
T cells to self-ligands is associated with upregulation of
various activation/memory markers; in some but not all
studies, the expression of these markers is maintained
when total T cell numbers return towards normal values
(reviewed in [77]).
The important implication of these findings is that some
typical memory-phenotype T cells are not the progeny of
cells responding to various environmental antigens but
instead arise through homeostatic proliferation directed to
self-antigens. As homeostatic proliferation of na?ve T cells
is minimal in normal young mice (which have large num-
bers of na?ve T cells), the proportion of self-ligand-selected
?pseudo?-memory cells is probably quite low in normal ani-
mals. However, it is quite conceivable that these cells
become prominent when total T cell numbers are reduced,
for example, after cytoreductive treatment for cancer, in
patients with HIV infection and perhaps in normal aging
(where na?ve T cells decline in number and are replaced by
memory cells). Because homeostatic proliferation is poly-
clonal, the pseudo-memory cells generated in response to
self-antigens presumably express an extensive crossreactive
repertoire for foreign antigens.
Factors controlling the survival of memory cells
MHC ligands
There is now increasing evidence that, as for na?ve cells,
the long-term survival of memory cells is not a passive
process but reflects continuous T cell stimulation.
However, the factors controlling the survival of na?ve and
memory T cells seem to be different. For na?ve T cells,
most [73,80,81
?
], but not all [79,82], of the available evi-
dence indicates that the survival of these cells requires
continuous contact with self-MHC−peptide ligands. It was
initially reported that interaction with MHC ligands is also
required for the survival of T memory cells, albeit with less
fine-specificity than for na?ve cells [73]; however, more
recent evidence suggests that memory T cells can survive
in the absence of MHC molecules (MHC class I for CD8
+
cells, MHC class II for CD4
+
cells) [81
?
,83
?
], implying that
survival does not depend on TCR ligation; for CD4
+
cells,
this issue is still controversial because some workers main-
tain that the survival of memory CD4
+
cells requires
persistent contact with residual antigen [84].
Page 4
Generation and maintenance of memory T cells Sprent and Surh 251
Cytokines
At least for CD8
+
cells, loss of contact with MHC ligands
does not interfere with the high background rate of mem-
ory cell proliferation [81
?
]. This finding suggests that
memory cells are subjected to stimulation by other (non-
MHC) ligands. Here, the role of cytokines is receiving
increasing attention. Currently, the notion that cytokines
control the survival of memory cells is largely restricted to
CD8
+
cells. For these cells, it was initially found that the
background rate of memory CD8
+
cell proliferation
increased sharply after injection of mice with compounds
such as Poly IC [85] and lipopolysaccharide [86]. These
compounds are not recognized by the TCR but lead to
strong production of cytokines, for example IFN-I and
IFN-γ, by APCs and other cells. Because IFN-I and IFN-γ
do not stimulate purified T cells in vitro, it was reasoned
that these cytokines elicit ?bystander? (non-TCR-depen-
dent) proliferation of memory CD8
+
cells in vivo through
synthesis of an additional cytokine, in other words, an
effector cytokine that acts directly on CD8
+
memory cells.
There is now strong evidence that the effector cytokine is
IL-15 [87]; this cytokine is made by many types of cells,
including APCs, but is not synthesized by T cells [88].
First, IL-15 is directly stimulatory for purified CD8
+
mem-
ory cells and elicits strong proliferation of these cells, both
in vitro and in vivo [89]; in mice, IL-15 is only poorly stim-
ulatory for CD4
+
memory cells and is non-stimulatory for
na?ve cells. Second, IL-15 transgenic mice show a selective
enrichment of CD8
+
memory cells [56,90
?
]. Third, the
selective action of IL-15 on CD8
+
memory cells correlates
with high expression of IL-2Rβ (CD122), an important
receptor for IL-15 (and IL-2) [89,91
?
]; CD122 expression is
much lower on CD4
+
memory cells and also on na?ve
T cells. Fourth, compounds that elicit bystander prolifera-
tion of CD8
+
memory cells (Poly IC, lipopolysaccharide,
IFN-I, IFN-γ) induce synthesis of IL-15 by APCs [89].
Fifth, IL-15Rα
?
[92] and IL-15
?
[93
?
] mice show a selective
reduction in the proportion of CD8
+
memory cells. Sixth,
injecting mice with anti-CD122 monoclonal antibody
reduces the turnover of CD8
+
memory cells [91
?
]; con-
versely, injecting anti-IL-2 monoclonal antibody enhances
proliferation of these cells, which leads to the interesting
conclusion that stimulation of CD8
+
cells by IL-15 is nor-
mally balanced by an inhibitory influence of IL-2 [45
?
,91
?
].
Collectively, these data suggest that IL-15 has a key role in
regulating homeostasis of CD8
+
memory cells, both by
inducing intermittent proliferation of these cells and by
maintaining cell viability. Despite the importance of
IL-15, it remains possible that other cytokines contribute
to the survival of CD8
+
memory cells. On this point, it is
notable that IL-15Rα
?
and IL-15
?
mice both show only a
partial (2?3-fold) reduction in CD44
hi
CD8
+
cells [92,93
?
].
Interestingly, in IL-15
?
mice the residual CD44
hi
CD8
+
cells are nearly all CD122
lo
(A Judge, J Sprent, unpub-
lished data). The implication therefore is that the subset of
CD122
lo
CD44
hi
CD8
+
cells, which comprises about 30% of
CD44
hi
CD8
+
cells in normal mice, is relatively indepen-
dent of IL-15. How CD122
lo
CD44
hi
CD8
+
cells are kept
alive is still unknown.
It should be emphasized that most of the data on the role
of IL-15 on memory T cell survival are based on studies
with normal ?memory-phenotype? cells rather than on cells
carrying memory for defined antigens. Because typical
antigen-specific memory CD8
+
cells are CD122
hi
, it would
seem quite likely that the long-term survival of these cells
is IL-15-dependent; however, direct evidence on this
question is lacking. Thus, it is conceivable that a compo-
nent of CD8
+
memory could be carried by the minor
subset of CD122
lo
CD8
+
cells. Evidence against this possi-
bility has come from the interesting finding that the
lifespan of memory CD8
+
cells generated from antigen-
stimulated cells in vitro is heavily influenced by the
cytokine milieu encountered in culture [94
?
]. Thus, some
cytokines, notably IL-4, stimulated the production of long-
lived memory cells; by contrast, other cytokines, for
example IL-2, generated memory cells that disappeared
progressively over a period of several weeks. The key find-
ing was that, for these two cytokines, only IL-4 and not
IL-2 caused upregulation of CD122 on the precursor cells
in culture. The implication therefore is that memory cells
are relatively short lived unless the cells are induced to
express high levels of CD122 during the primary response;
CD122 expression makes the cells responsive to IL-15 and
thus ensures their long-term survival.
As many infectious organisms lead to strong production of
IFNs, infection would be expected to induce bystander
activation of pre-existing memory CD8
+
cells [85]. The
evidence on this point is conflicting. Thus, some groups
find that bystander proliferation of memory CD8
+
cells
induced by non-crossreactive viruses is very limited or
undetectable [13,14,95,96]; in fact, bystander activation
can lead to T cell apoptosis rather than proliferation, thus
leading to attrition of memory cells [97]. However, other
workers do find evidence of considerable bystander prolif-
eration during the early (but not late) stages of viral
infections [98]. In view of these conflicting data, the issue
of how bystander stimuli induce quantitative or qualitative
alterations in the pool of pre-existing memory CD8
+
cells
has yet to be resolved. Nevertheless, the fact that numbers
of antigen-specific memory CD8
+
cells remain relatively
constant throughout life indicates that memory cells are
subject to strict homeostatic control [99], bystander prolif-
eration and death being equally balanced.
The above data refer to memory CD8
+
cells ? much less is
known about the factors controlling the survival of memory
CD4
+
cells. It would seem quite likely that, as for CD8
+
cells, contact with cytokines is required for the long-term
survival of memory CD4
+
cells. However, which cytokines
are involved is unknown although IL-15 would seem to be
excluded [92,93
?
]. It is notable that, like CD8
+
cells, mem-
ory CD4
+
cells are susceptible to bystander activation by
Page 5
252 Lymphocyte development
IFNs [100]; the effector cytokines involved in this response
are still unclear.
Conclusions
The generation of memory T cells can be viewed as the
culmination of a complex life/death struggle: most T cells
participating in the primary response are rapidly eliminat-
ed, leaving only a small proportion of these cells to survive
as long-lived memory cells. How memory precursors evade
death in the primary response remains a mystery. Perhaps
the simplest idea is that death is the default pathway and
that the survival of memory cells involves an instructional
process. However, it is striking that a wide variety of gene-
knockout mice develop progressive T cell hypertrophy of
the secondary organs, implying that many different mole-
cules in, or on, T cells are essential for destroying T cells.
Hence the default pathway for T cells at the end of the pri-
mary response may be survival, not death.
A key issue is whether memory T cells arise from fully differ-
entiated effector cells or from partly differentiated cells.
Although definitive information on this question is still lack-
ing, several recent studies indicate that memory cells can arise
from precursors that display clear signs of effector activity, for
example synthesis of cytokines and perforin. The relationship
of these effector-memory precursors to typical end-stage,
short-lived effector cells, however, has yet to be resolved.
Once formed, memory T cells often survive indefinitely at
a population level yet display considerable heterogeneity
in terms of their activation status, migratory properties and
expression of surface molecules, notably CCR7 chemokine
receptors. Whether the survival of memory cells requires
contact with extrinsic stimuli is receiving close attention.
The bulk of evidence suggests that, unlike na?ve T cells,
memory T cells do not require continuous contact with
MHC ligands. However, for CD8
+
cells, there is good evi-
dence that memory cell survival requires contact with
cytokines, notably IL-15. Whether CD4
+
memory cells are
cytokine dependent is still unclear.
Acknowledgements
We would like to thank Claudia Meo and Barbara Marchand for typing and
handling the manuscript. This work was supported by the US Public Health
Service grants AI21487, CA38355 and AI46710 to JS and AI41079 and
AI45809 to CDS. CDS is a Scholar of The Leukemia & Lymphoma Society.
Publication number 13723-IMM from the Scripps Research Institute.
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254 Lymphocyte development