| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Molecular Immunology, National Institute for Medical Research, London, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-chain have been shown to be important in
providing survival signals for naive T cells (11).
Specifically, IL-7 has been implicated as an essential survival factor
in vivo (12, 13). Naive T cells also have the capacity to proliferate in response to conditions of lymphopenia, while largely maintaining a naive phenotype, as part of a homeostatic response to T cell deficiency. This occurs in mice following thymectomy (14), but is also seen following adoptive transfer of T cells into hosts rendered lymphopenic by sublethal irradiation or into hosts lacking T cells through genetic defects (8, 15, 16, 17, 18). The signals that drive this homeostatic proliferation are similar to those that mediate survival. In lymphopenic hosts, interactions of the TCR with self MHC Ags induce T cells to proliferate (8, 15, 16, 17). Moreover, recent studies have shown that IL-7 also plays an important role in stimulating homeostatic proliferation in T cells transferred to lymphopenic hosts (13, 19), and it has been suggested that, as is the case for T cell survival, induction of homeostatic proliferation requires concurrent activation of both IL-7R and TCR signaling pathways.
Previous studies in this laboratory using mice bearing an inducible p56lck (lck) transgene (20) have shown that, in contrast to survival signals, the TCR signals that induce homeostatic proliferation have an absolute requirement for the expression of lck (21). In the present study we show that even when TCR signaling is abrogated by the absence of both src family kinases, lck and fyn, IL-7R-mediated signals are able to drive homeostatic proliferation under conditions of acute lymphopenia. Therefore, stimulation of naive T cells through either the TCR or IL-7R signaling pathway can independently result in homeostatic proliferation with distinct kinetics and duration. While the overall response is a synergy of these combined signals, the relative contribution of these pathways depends on both the degree of lymphopenia and the relative responsiveness of individual T cell clones to these two stimuli.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Generation of inducible lck transgenic mice has been described
previously (20). Mice were fed doxycycline
(dox)3 in food (1
mg/g) to maintain lck transgene expression.
Lck1indfynneg mice were
derived by intercrossing
rtTA-Chom/lckneg/fynneg
and
Lck1hom/lckneg/fynneg
strains. F5homrecombinase-activating gene
(RAG)neg,
F5homRAGnegfynneg,
lcknegfynneg,
lcknegfyn+/-,lckneg,
RAGneg, class
IInegRAGnegcneg,
and C57BL/10 mice were bred in a conventional colony free of pathogens
at the National Institute for Medical Research (London, U.K.).
Purification, labeling, and adoptive transfer of T cells
Lymphocytes were teased from lymph nodes of donor mice, and
single-cell suspensions were prepared. For experiments requiring
purified T cell preparations, lymphocytes were labeled with 100
µl/107 cells of a mixture of
anti-B220-biotin (BD PharMingen, San Diego, CA) and
anti-I-Ab-biotin (BD PharMingen) at 1 µg/ml
for 30 min at 4°C. After washing, cells were incubated with
M280-streptavidin Dynal beads (Dynal, Chantilly, VA) for 30 min, after
which cells were separated by application of a magnet. Contaminating
class II MHC expressing or B220+ cells were
consistently <1%. Cells were labeled with 1 µM CFSE (Molecular
Probes, Eugene, OR) in Dulbecco’s PBS (Life Technologies, Grand
Island, NY) for 10 min at 37°C and washed twice. Cells were
transferred into various recipient mice via tail vein injections.
Treatment of recipient mice with purified 
IL-7R mAb (A7R34) in PBS
was performed on a 7-day cycle of i.p. injections of 300 µg/mouse of
mAb on days 1, 3, and 5 for the duration of the experiment.
Controls received injections of PBS alone. Successful treatment
with IL-7R Ab was determined by showing that B cell
development was completely blocked in the bone marrow of
recipientlcknegfynneg
mice. Immature B220lowIgM-
(R1) and B220lowIgM+ (R2)
subsets were ablated compared with those in PBS-treated controls,
leaving only a population of mature
B220highIgM+ cells (Fig. 2
A).
|
Flow cytometry was conducted using 106
thymocytes or lymph node cells. Cells were incubated with saturating
concentrations of Abs in 100 µl PBS/BSA (0.1%)/azide (1 mM) for
1 h at 4°C, followed by three washes in PBS/BSA/azide.
Biotin-conjugated Ab labeling was developed with streptavidin-PE-Cy7
(Caltag, Burlingame, CA). For recipients of CFSE-labeled T cells, cell
suspensions were prepared from superficial cervical, brachial, axilary,
inguinal, and mesenteric lymph nodes of individual mice. Up to 3
x 107 lymph node cells were labeled with the
indicated Abs at saturating concentrations in 20
µl/106 cells. The mAbs used in this study were
as follows: PE-CD4 (GK1.5; BD PharMingen), PerCP-CD8 (53-6.7; BD
PharMingen), allophycocyanin-CD8 (53-6.7; BD PharMingen), FITC-TCR
(H57-597; BD PharMingen), allophycocyanin-TCR (H57-597; BD PharMingen),
biotin-CD44 (Pgp-1), biotin-IL-7R (A7R34), allophycocyanin-B220
(RA3-6B2; BD PharMingen), and PE-IgM (BD PharMingen). Negative control
samples for biotin-IL-7R staining were performed by incubation of
cells with unlabeled IL-7R mAb before labeling with biotin-IL-7R
and streptavidin-PE-Cy7.
Four-color cytometry staining was analyzed on a FACSCalibur instrument (BD Biosciences, Mountain View, CA), and data analysis was performed with CellQuest software (BD Biosciences).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To assess the role of TCR signals in driving homeostatic proliferation of naive T cells, we examined the behavior of T cells from mice with an inducible lck transgene (20). These mice have an lck transgene under a tetracycline-sensitive promotor (Lck1) and a second tet-on trans-activator domain (rtTA-C) transgene under control of human CD2 regulatory elements, targeting expression to T cells. Since Lck1/rtTA-C/lckneg (Lck1ind mice) fail to express endogenous lck, all lck expression can be controlled by administration of the tetracycline derivative dox. Feeding dox throughout the lives of Lck1ind mice restores lck expression and allows reconstitution of normal thymopoiesis and population of the peripheral T cell pool (20).
We showed previously that continued lck transgene expression
was essential to transduce the TCR signals responsible for homeostatic
proliferation (21). In these studies
lckneg mice, which are only partially T
cell deficient, were used as hosts for the adoptive transfer of T cells
from Lck1ind mice. To determine the requirement
for TCR signals to drive homeostatic proliferation in conditions of
more severe T cell deficiency, cells were transferred to recipients
lacking the expression of both lck and another src family
kinase, p59fyn (fyn). These mice
exhibit a complete block in thymic development and, in contrast to
lckneg mice, have no peripheral T cells
(22, 23). T cells from wild-type (WT) and
Lck1ind mice were purified, labeled with the dye
CFSE, and transferred into syngeneic
lcknegfynneg
hosts. Recipients of T cells from Lck1ind mice
were either fed dox, to maintain lck transgene expression,
or not, in which case lck transgene expression was lost
within 2 days from peripheral T cells (B. Seddon, unpublished
observations) (21). Analysis of CFSE fluorescence in
individual cells allows their proliferative behavior to be determined
for up to six cell divisions, after which dye levels are below the
range of detection. Typically the recoveries of naive T cells from
these animals was between 3–5% of input cell number, but importantly
we saw no significant differences in the efficiency of recovery that
correlated with either the lymphocyte donor or the recipient mouse
genotypes. In addition to the populations undergoing division, a large
population of CFSE-negative TCR+ cells,
representing cells that had undergone seven or more divisions was
observed (Fig. 1). These cells were
CD44high and most likely derived from the memory
cell constituent of the transferred T cells, which divided rapidly
following transfer. Purification of CD44low naive
cells did not completely exclude the appearance of this population
after transfer (data not shown), and as these cells were excluded from
the CFSE-positive gate and did not interfere with the analysis of
CD44low naive cell responses, unfractionated T
cells were used throughout this study.
|
A, left
column), and a similar pattern of cell divisions was observed in T
cells from Lck1ind mice transferred to dox-fed
recipients (Fig. 1A, middle column).
Surprisingly, in the absence of continued lck expression (-dox, Fig. 1A, right columns) both
CD4+ and CD8+ T cells from
Lck1ind mice underwent significant proliferation,
although this was generally less than that of WT T cells. Proliferation
was not mediated by residual lck in these cells, as the low
levels of lck expressed by Lck1ind
peripheral T cells are completely lost within 48 h after dox
removal (data not shown), while most proliferation in this situation is
observed between days 7 and 14. Furthermore, cells from mice that had
been off dox for 4 wk before transfer showed an equivalent number of
divisions (Fig. 1A). While
lcknegfynneg
mice were used throughout the present study as completely empty hosts,
T cells from WT or Lck1ind donor mice behaved in
an identical way when transferred into RAGneg
mice, which lack both T and B cells.
We have shown previously that lck is required to transduce
the TCR signals that induce homeostatic proliferation
(21). Therefore, we considered that this
lck-independent proliferation might not be TCR mediated.
This possibility was assessed in two ways. Firstly, homeostatic
proliferation of lck-deficient T cells in hosts lacking
specific MHC ligands was assessed. Lymph node T cells from either WT or
Lck1ind mice were rigorously depleted of class
II-expressing cells, CFSE labeled, transferred into dox-free class II
MHCnegRAGnegcneg
hosts, which lack host T cells, class II MHC ligands, and NK cells, and
were analyzed after 2 wk. Both lck-deficient and WT
CD4+ T cells proliferated in an identical way in
the absence of class II MHC ligands, while remaining
CD44low over this time period (Fig. 1B). Secondly, the behavior of T cells from
Lck1ind mice that also lack
p59fyn (fyn) was assessed. In the
absence of both transgenic lck and endogenous fyn
expression, T cells fail to survive long term (29) due to
an inability to transduce TCR-mediated survival signals. However, naive
cells survive long enough to assess their proliferative response upon
transfer into T cell-deficient recipients. T cells from either
Lck1ind or Lck1ind
fynneg mice were CFSE labeled and transferred
into empty
lcknegfynneg
recipients in the absence of dox. After 2 wk, analysis of lymph nodes
of recipient mice showed that CD4+ T cells from
Lck1ind fynneg mice
proliferated to an equivalent extent as T cells from
Lck1ind mice despite lacking the expression of
both lck and fyn (Fig. 1C). Together,
these data clearly illustrate that homeostatic proliferation in T
cell-deficient hosts can occur in the complete absence of TCR-mediated
signals.
TCR and IL-7R signals drive homeostatic proliferation in T cell-deficient hosts
Recent studies have highlighted a role for IL-7 in the homeostatic
proliferation of naive T cells (13, 19). Therefore, we
asked whether lck-independent proliferation by
Lck1ind T cells in T-deficient hosts might be
mediated by IL-7. T cells from WT and Lck1ind
mice were CFSE labeled and transferred into empty
lcknegfynneg
hosts. The effect of IL-7 on donor T cells was assessed by treating
groups of recipient mice with repeated injections of an Ab that binds
IL-7R (IL-7R), thereby inhibiting the biological activity of IL-7 in
vivo. We could confirm that the IL-7R Ab was at saturating levels by
showing that B cell development was completely blocked in the bone
marrow of recipient
lcknegfynneg
mice. Immature B220lowIgM-
(R1) and B220lowIgM+ (R2)
subsets were ablated compared with PBS-treated controls (Fig. 2A, right
column), leaving only a population of mature
B220highIgM+ cells.
Analysis of lymph node T cells from host mice 10 days after transfer
showed that blockade of IL-7R resulted in a considerable reduction in
the proliferation of WT cells, reflected by the increased size of the
undivided peak, particularly in the CD4+ subset
(Fig. 2A). Strikingly, proliferation of T cells from
Lck1ind mice in dox-free
lcknegfynneg
hosts was essentially abrogated by treatment with the IL-7R mAb
(Fig. 2B). Significantly, these data show that homeostatic
proliferation of naive T cells in T cell-deficient hosts can be
completely accounted for by a combination of lck- and
IL-7R-mediated signals.
Titration of T cell space in different combinations of lck and fyn deficiencies
The data described to date show that homeostatic proliferation can
be induced by activation of the IL-7R signaling pathway independently
of signals through the TCR. However, we showed previously that the
presence of as little as 14% of the normal T cell cohort (i.e., in
lckneg hosts) prevented this expansion in
the absence of lck-mediated TCR signals (21).
Therefore, we examined the relative contributions of TCR- and
IL-7R-mediated signals under a range of lymphopenic conditions of
increasing severity. CFSE-labeled T cells from WT and
Lck1ind mice were transferred into mice that were
1) WT for lck and fyn (47% T cells in peripheral
LN), 2)
lcknegfyn+/+
(14% of WT T cell numbers), 3)
lcknegfyn+/-
(3% of WT T cell numbers), and 4)
lcknegfynneg
(<1% of WT T cell numbers). Mice receiving
Lck1ind T cells were taken off dox to switch off
lck expression, and all recipients were analyzed on day 33.
As expected, WT T cells transferred into full
fyn+/+lck+/+
hosts did not undergo homeostatic proliferation (Fig. 3A), whereas the same cells
transferred to the various lckneg
lymphopenic hosts proliferated in an increasing manner that reflected
the degree of T cell deficiency in the recipient (Fig. 3, B–D). A useful indicator of the extent of proliferation was
obtained from the relative size of the undivided peak in each of the
hosts, which became smaller as host T cell numbers were reduced.
Lck1ind T cells in which lck
expression was maintained by dox feeding behaved comparably to WT cells
(21).
|
D). However, proliferation of T cells lacking
lck was far more sensitive than WT cells to the presence of
host T cells, such that as few as 3% of normal T cell numbers present
in
lcknegfyn+/-
hosts was sufficient to dramatically reduce IL-7-mediated proliferation
(Fig. 3C). The presence of 14% of normal T cell numbers
(lcknegfyn+/+
hosts) was sufficient to completely inhibit IL-7-driven proliferation
(Fig. 3B). Competition for IL-7 limits the extent of IL-7R-driven proliferation
Since IL-7R-driven proliferation is sensitive to so few host T
cells, we asked whether this sensitivity would ultimately limit the
extent to which T cells could proliferate. We compared the kinetics of
IL-7R- vs TCR-induced proliferation by transfer of CFSE-labeled T cells
from WT and Lck1ind mice to dox-free
lcknegfynneg
hosts and assessed proliferation on days 16 and 33. In the absence of
lck, T cells from Lck1ind mice
underwent an initial burst of proliferation within the first 16 days,
but underwent very little further division between days 16 and 33 (Fig. 4A). In contrast, WT
CD4+ and CD8+ T cells
continued to proliferate between days 16 and 33 (Fig. 4A).
This suggests that the IL-7R-induced component is relatively
short-lived, and expansion after 
day 14 relies on a competent TCR
signaling component. A possible explanation for the short-lived nature
of IL-7R-driven proliferation is that the expansion of donor T cells
results in either competition for or consumption of available IL-7,
such that signaling through IL-7R alone becomes insufficient to drive
further proliferation. Alternatively, the transferred T cells may
became refractory to stimulation through IL-7R in the absence of
additional TCR signals.
|
Bii). As a control,
untreated
lcknegfynneg
hosts were injected with CFSE-labeled T cells from
Lck1ind mice, and
CD4+CD44low lymph node
cells of recipients were examined 14 and 28 days after cell transfer
(Fig. 4Bi). Consistent with the previous experiment (Fig. 4A), donor T cells in unconditioned recipients underwent
several divisions within the first 14 days, but were little changed
thereafter (Fig. 4Bi). Significantly, preconditioning with
unlabeled T cells, seen as the CFSE-negative peak in Fig. 4Bii, was sufficient to prevent division of CFSE-labeled
lck-negative T cells. The failure of freshly transferred T
cells to proliferate in these hosts suggests that IL-7 was not
available at a level sufficient to induce proliferation as a result of
the prior transfer of unlabeled Lck1ind T cells.
Therefore, the data support the view IL-7R-driven proliferation is
limited by competition for IL-7 following expansion of donor T
cells. F5 TCR transgenic T cells require lck, but not fyn, to induce homeostatic proliferation
To further examine the influence of src family kinases and IL-7 on homeostatic proliferation we moved to a monoclonal TCR population, F5 RAGneg TCR transgenic mice, which bear a class I MHC-restricted TCR specific for influenza nucleoprotein peptide. F5 RAGneg mice with the inducible lck transgene were generated (F5 RAGnegLck1indlckneg). Induction of lck in these mice restores normal generation of peripheral transgenic T cells, overcoming a block in thymic development observed in the absence of lck (data not shown). The specific signaling requirements for homeostatic proliferation of F5 T cells were examined by transferring CFSE-labeled lymph node cells from F5 RAGnegLck1ind into lcknegfynneg recipients with or without dox. Additionally, we compared whether there was a requirement for the expression of fyn by similarly transferring CFSE-labeled T cells from F5 RAGnegfynneg donors. Control mice received CFSE-labeled T cells from F5 RAGneg mice.
Analysis of lymph nodes at 14 day (Fig. 5) showed that, as seen with polyclonal
cells, both F5 RAGneg (Fig. 5A) and
dox-fed F5 RAGnegLck1ind
(Fig. 5C) donor T cells underwent homeostatic proliferation.
In contrast to the requirement for lck, proliferation in the
absence of fyn (Fig. 5B) was at least equivalent
to and even slightly increased compared with that in WT F5 cells (Fig. 5A). Surprisingly however, F5
RAGnegLck1ind T cells
demonstrated a total dependence on lck for any proliferative
response even in these acutely lymphopenic hosts (Fig. 5D).
Thus, the behavior of lckneg F5 T cells differs
from that of the majority of polyclonal CD8+
cells (Fig. 1), in that proliferation does not occur to IL-7R signals
alone and instead is entirely dependent on the expression of lck. An
explanation for this was revealed by examination of IL-7R expression by
F5 T cells, which was greatly reduced compared with that by polyclonal
B10 controls even though expression appeared normal in double-negative
and double-positive F5 thymocytes (Fig. 6). However, this low level IL-7R
expression in peripheral F5 T cells was evidently sufficient to provide
survival signals, as similar numbers of F5 and WT T cells were
recovered 14 days after their transfer to T cell-deficient hosts (data
not shown).
|
|
Since the expression of IL-7R in F5 T cells is by itself too low
to induce homeostatic proliferation, we were able to address the
question of whether we could observe synergy between TCR and IL-7R
signals for the overall proliferative response in WT F5 T cells. T
cells from F5 RAGneg mice were CFSE labeled and
transferred into
lcknegfynneg
recipients treated with either PBS or repeated injection of IL-7R
mAb to block IL-7R activity in vivo. At 7 and 14 days after transfer,
lymph node cells were taken and analyzed. T cells transferred into
PBS-treated recipients underwent at least five divisions during the
14-day period. Significantly, treatment of mice with IL-7R mAb
greatly reduced the number of divisions undergone by F5 T cells (Fig. 7). These data strongly suggest that
IL-7R-mediated signals were indeed providing a positive signal to
facilitate TCR-mediated homeostatic expansion by F5 T cells,
demonstrating a synergy between IL-7R and TCR signals. Finally, these
data confirm that TCR-mediated signals are sufficient to induce
homeostatic expansion in the absence of contributions from the
IL-7R.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Earlier reports have suggested that induction of homeostatic
proliferation requires coincident activation of both TCR and IL-7R
pathways (13), and consistent with this, we observed
greatest proliferation when both TCR and IL-7R pathways were active
(Fig. 1). However, we also found that proliferation could, in fact, be
induced by independent activation of either TCR or IL-7R signaling
pathways. Neither an absence of host class II MHC ligands nor
inactivation of TCR signaling by loss of lck and
fyn expression prevented IL-7R-induced proliferation (Fig. 1), and conversely, complete IL-7R blockade did not prevent
TCR-mediated proliferation (Figs. 2 and 7). Assessing the contributions
of these two triggers of homeostatic proliferation in response to
varying degrees of lymphopenia revealed different roles for these
signals. TCR signals induced sustained proliferation over the range of
conditions tested. In contrast, IL-7R signals induced proliferation
only in the most lymphopenic hosts. It appears that induction of
TCR-independent proliferation requires a critical threshold of IL-7R
signaling that cannot be achieved in hosts with low numbers of T cells
(Figs. 3 and 4), in which there is presumably competition for IL-7, and
this may explain why this proliferation is ultimately self limiting
(Fig. 4A). It is significant to note that IL-7 has been
shown to play a major role in driving proliferation in sublethally
irradiated hosts (13, 19) that still contain residual host
T cells, suggesting that irradiation may stimulate an increase in IL-7
production. Indeed, we also found that Lck1neg T
cells proliferate vigorously in sublethally irradiated hosts,
confirming that in this environment proliferation can occur
independently of TCR-induced signals (our unpublished
observations).
Although we demonstrate that IL-7 and TCR signals can operate
independently, we were able also to show synergy and not simply an
additive effect of these signals. Under conditions where IL-7 was
unable to directly induce TCR-independent proliferation in F5
RAGneg T cells, it was apparent that IL-7R
signals synergized with TCR signals to drive stronger proliferation
than that mediated by TCR signals alone (Fig. 7). The point at which
these signals interact is not known. The proliferation in response to
IL-7R triggering clearly occurs in the absence of either lck
or fyn (Fig. 1), whereas the TCR component has an absolute
requirement for lck, but, interestingly, not fyn,
suggesting distal activation of a common program of cell division,
rather than an influence on the sensitivity of the TCR to self-Ag.
Consistent with this view, the expression of CD5, used as an indicator
of TCR survival signals, is not influenced by blocking IL-7R (our
unpublished observations).
The status of the naive T cell is also an important consideration, as
demonstrated by the experiments involving Lckneg
F5 T cells, which express only low levels of IL-7R (Figs. 5 and 6) and
fail to respond to IL-7 signals in the absence of contributory
signaling through the TCR. It is also worth noting that not all
polyclonal T cells respond to IL-7R signals, as we found that in the
absence of lck expression a significant proportion of
CD4+ and CD8+ cells failed
to proliferate. By the same token, not all T cell specificities may be
able to respond to self-MHC peptide complexes or even the synergistic
combination of both of these signals. Furthermore, whether this
proliferation results in up-regulation of markers such as CD44 varies
and presumably reflects the avidities of individual T cells. It is
likely that individual TCR transgenic mice represent a subset of the
polyclonal repertoire, exhibiting either a responsive (e.g., OT-1
(19)), partially responsive (e.g., F5 (18)),
or nonresponsive (e.g., H-Y (5)) phenotype, rather than
being representative of the entire T cell population. However, these
TCR transgenic examples are valuable for illustrating the
characteristics of individual T cells that contribute to their ability
to divide in response to lymphopenia and need to be considered together
with the status of the host environment.
The preceding discussion may also explain apparent contradictions
between our observation that IL-7R signals and TCR signals can drive
homeostatic proliferation independently of one another and those of
other groups who showed that proliferation of polyclonal and OT-1 TCR
transgenic T cells was abrogated in IL-7-deficient hosts (13, 19). Additionally, these studies monitored proliferation over 7
days, while we followed the behavior of T cells over a longer time
period. Significantly, proliferation of F5 T cells in IL-7R-treated
hosts at d7 (Fig. 7) appears very similar to that described for OT-1 T
cells in IL-7-deficient hosts, as the TCR-mediated drive is quite slow,
in contrast to that stimulated through IL-7R, and it is not until the
second week that significant proliferation is observed. In this regard
it is significant to note the low expression of IL-7R by F5 compared
with the high levels expressed by OT1 T cells (19) may
also contribute to the observed differences in their responsiveness to
IL-7R signals.
The signaling requirements for homeostatic proliferation, therefore,
contrast with those of T cell survival, even though the same
combination of TCR and IL-7R signals is involved. Fig. 8 suggests a model of how these signals
may be integrated for these two processes. Both TCR and IL-7R signals
are absolutely required for long term survival (29),
whereas either of these signals alone can initiate homeostatic
proliferation. Furthermore, we found no evidence that fyn
contributed to either IL-7R- or TCR-induced homeostatic proliferation,
whereas fyn plays a significant role in transducing TCR
survival signals (29). Finally, these data demonstrate
that the signaling pathway downstream of the IL-7R does not involve the
src family kinases lck and fyn.
|
|
Acknowledgments |
|---|
c-/- mice, Prof. S. Nishikawa for the
anti-IL-7R mAb A7R34, and to Brigitta Stockinger, George
Kassiotis, and Dimitris Koussis for critical reading of the manuscript
and discussion. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Rose Zamoyska, Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, U.K. NW7 1AA. E-mail address: rzamoys{at}nimr.mrc.ac.uk
3 Abbreviations used in this paper: dox, doxycycline; RAG, recombinase-activating gene; WT, wild type.
Received for publication May 1, 2002. Accepted for publication August 2, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
chain required for naive CD4+ T cell survival but not for antigen proliferation. Nat. Immunol. 1:54.[Medline]
T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity 5:429.[Medline]
This article has been cited by other articles:
|
|
 |
|
  M. Saini, C. Pearson, and B. Seddon Regulation of T cell-dendritic cell interactions by IL-7 governs T-cell activation and homeostasis Blood, June 4, 2009; 113(23): 5793 - 5800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Opiela, T. Koru-Sengul, and B. Adkins Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants Blood, May 28, 2009; 113(22): 5635 - 5643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. I. Azevedo, M. V. D. Soares, J. T. Barata, R. Tendeiro, A. Serra-Caetano, R. M. M. Victorino, and A. E. Sousa IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner Blood, March 26, 2009; 113(13): 2999 - 3007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Rettig, L. McNeill, N. Sarner, P. Guillaume, I. Luescher, M. Tolaini, D. Kioussis, and R. Zamoyska An Essential Role for the Stalk Region of CD8{beta} in the Coreceptor Function of CD8 J. Immunol., January 1, 2009; 182(1): 121 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Rochman and W. J. Leonard The Role of Thymic Stromal Lymphopoietin in CD8+ T Cell Homeostasis J. Immunol., December 1, 2008; 181(11): 7699 - 7705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Jay, L. M. Reed-Loisel, and P. E. Jensen Polyclonal MHC Ib-Restricted CD8+ T Cells Undergo Homeostatic Expansion in the Absence of Conventional MHC-Restricted T Cells J. Immunol., March 1, 2008; 180(5): 2805 - 2814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yates, M. Saini, A. Mathiot, and B. Seddon Mathematical Modeling Reveals the Biological Program Regulating Lymphopenia-Induced Proliferation J. Immunol., February 1, 2008; 180(3): 1414 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Xiao, D.-m. Su, and N. R. Manley Atypical Memory Phenotype T Cells with Low Homeostatic Potential and Impaired TCR Signaling and Regulatory T Cell Function in Foxn1{Delta}/{Delta} Mutant Mice J. Immunol., December 15, 2007; 179(12): 8153 - 8163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Filby, B. Seddon, J. Kleczkowska, R. Salmond, P. Tomlinson, M. Smida, J. A. Lindquist, B. Schraven, and R. Zamoyska Fyn Regulates the Duration of TCR Engagement Needed for Commitment to Effector Function J. Immunol., October 1, 2007; 179(7): 4635 - 4644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Cho, O. Boyman, H.-O. Kim, B. Hahm, M. P. Rubinstein, C. Ramsey, D. M. Kim, C. D. Surh, and J. Sprent An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2 J. Exp. Med., August 6, 2007; 204(8): 1787 - 1801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Chatzidakis, G. Fousteri, D. Tsoukatou, G. Kollias, and C. Mamalaki An Essential Role for TNF in Modulating Thresholds for Survival, Activation, and Tolerance of CD8+ T Cells J. Immunol., June 1, 2007; 178(11): 6735 - 6745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Osborne, S. Dhanji, J. W. Snow, J. J. Priatel, M. C. Ma, M. J. Miners, H.-S. Teh, M. A. Goldsmith, and N. Abraham Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R{alpha} mutant mice J. Exp. Med., March 19, 2007; 204(3): 619 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. H. Nguyen, R. Zeiser, D. L. daSilva, D. S. Chang, A. Beilhack, C. H. Contag, and R. S. Negrin In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation Blood, March 15, 2007; 109(6): 2649 - 2656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buentke, A. Mathiot, M. Tolaini, J. Di Santo, R. Zamoyska, and B. Seddon Do CD8 effector cells need IL-7R expression to become resting memory cells? Blood, September 15, 2006; 108(6): 1949 - 1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Taylor, P. T. Walsh, D. F. LaRosa, J. Zhang, M. A. Burchill, M. A. Farrar, and L. A. Turka Constitutive Activation of STAT5 Supersedes the Requirement for Cytokine and TCR Engagement of CD4+ T Cells in Steady-State Homeostasis J. Immunol., August 15, 2006; 177(4): 2216 - 2223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Martin, C. Becourt, B. Bienvenu, and B. Lucas Self-recognition is crucial for maintaining the peripheral CD4+ T-cell pool in a nonlymphopenic environment Blood, July 1, 2006; 108(1): 270 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Staton, A. B. Carpenter, and S. H. Jackman IL-7 Is a Critical Factor in Modulating Lesion Development in Skn-Directed Autoimmunity J. Immunol., April 1, 2006; 176(7): 3978 - 3986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Mayack and L. J. Berg Cutting Edge: An Alternative Pathway of CD4+ T Cell Differentiation Is Induced Following Activation in the Absence of {gamma}-Chain-Dependent Cytokine Signals J. Immunol., February 15, 2006; 176(4): 2059 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. French, C. L. Roark, W. K. Born, and R. L. O'Brien {gamma}{delta} T cell homeostasis is established in competition with {alpha}{beta} T cells and NK cells PNAS, October 11, 2005; 102(41): 14741 - 14746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-E. Miranda-Carus, M. Benito-Miguel, M. A. Llamas, A. Balsa, and E. Martin-Mola Human T Cells Constitutively Express IL-15 That Promotes Ex Vivo T Cell Homeostatic Proliferation through Autocrine/Juxtacrine Loops J. Immunol., September 15, 2005; 175(6): 3656 - 3662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Herndler-Brandstetter, S. Schwaiger, E. Veel, C. Fehrer, D. P. Cioca, G. Almanzar, M. Keller, G. Pfister, W. Parson, R. Wurzner, et al. CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age J. Immunol., August 1, 2005; 175(3): 1566 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Fry and C. L. Mackall The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance J. Immunol., June 1, 2005; 174(11): 6571 - 6576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Min, H. Yamane, J. Hu-Li, and W. E. Paul Spontaneous and Homeostatic Proliferation of CD4 T Cells Are Regulated by Different Mechanisms J. Immunol., May 15, 2005; 174(10): 6039 - 6044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Lopez and N. Holmes Phenotypical and functional alterations in the mucosal immune system of CD45 exon 9 KO mice Int. Immunol., January 1, 2005; 17(1): 15 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Sullivan, L. M. Reed-Loisel, G. J. Kersh, and P. E. Jensen Homeostatic Proliferation of a Qa-1b-Restricted T Cell: A Distinction between the Ligands Required for Positive Selection and for Proliferation in Lymphopenic Hosts J. Immunol., November 15, 2004; 173(10): 6065 - 6071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rivino, M. Messi, D. Jarrossay, A. Lanzavecchia, F. Sallusto, and J. Geginat Chemokine Receptor Expression Identifies Pre-T Helper (Th)1, Pre-Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells J. Exp. Med., September 20, 2004; 200(6): 725 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Sojka, D. Bruniquel, R. H. Schwartz, and N. J. Singh IL-2 Secretion by CD4+ T Cells In Vivo Is Rapid, Transient, and Influenced by TCR-Specific Competition J. Immunol., May 15, 2004; 172(10): 6136 - 6143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cozzo, J. Larkin III, and A. J. Caton Cutting Edge: Self-Peptides Drive the Peripheral Expansion of CD4+CD25+ Regulatory T Cells J. Immunol., December 1, 2003; 171(11): 5678 - 5682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Burchill, C. A. Goetz, M. Prlic, J. J. O'Neil, I. R. Harmon, S. J. Bensinger, L. A. Turka, P. Brennan, S. C. Jameson, and M. A. Farrar Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells J. Immunol., December 1, 2003; 171(11): 5853 - 5864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Grandjean, L. Duban, E. A. Bonney, E. Corcuff, J. P. Di Santo, P. Matzinger, and O. Lantz Are Major Histocompatibility Complex Molecules Involved in the Survival of Naive CD4+ T Cells? J. Exp. Med., October 6, 2003; 198(7): 1089 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cavalieri, S. Cazzaniga, M. Geuna, Z. Magnani, C. Bordignon, L. Naldini, and C. Bonini Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence Blood, July 15, 2003; 102(2): 497 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Geginat, A. Lanzavecchia, and F. Sallusto Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines Blood, June 1, 2003; 101(11): 4260 - 4266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Martin, C. Bourgeois, N. Dautigny, and B. Lucas On the role of MHC class II molecules in the survival and lymphopenia-induced proliferation of peripheral CD4+ T cells PNAS, May 13, 2003; 100(10): 6021 - 6026. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, IL-7R
expression.
