| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pathology, University of Miami Medical School, Miami, FL 33136
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In support of the idea that neonatal T cells are unique, many reports
have shown that there are phenotypic differences between neonatal and
adult T cells. Some of these differences could be predicted to limit
the functions of neonatal T cells. As one example, murine neonatal T
cells have TCR with limited N region addition (2, 3, 4) that restricts the
diversity of the TCR during the neonatal period. In vitro functional
studies have also lent support to the idea that neonatal T cells were
different from adult T cells. We earlier showed that, unlike naive
adult T cells, murine neonatal T cells make little IL-2 or IFN-
, but
high levels of IL-4 in response to primary stimulation in vitro (5, 6).
Thus, neonatal T cells appeared to be heavily biased toward Th2
responses in vitro. Subsequent reports indicated that the skewing to
Th2 responses seen in vitro may accurately reflect the activities of
neonatal T cells in vivo. First, there is convincing evidence that
neonatal tolerance is mediated by alloantigen-reactive, IL-4-producing
cells (7, 8). Tolerance to alloantigens in the newborn may then be
achieved by the suppressive effects of Th2 cells on Th1 cell-mediated
immunity. Second, it was reported recently (9, 10) that priming with Ag
during the neonatal period leads to secondary responses skewed heavily
toward Th2 responses. Thus, there is a good deal of evidence supporting
the theory that neonates are strongly biased toward Th2 responses both
in vitro and in vivo.
Recently, three different groups reported that mice initially exposed
to Ag as neonates displayed protective Th1 responses when they were
challenged as adults. Ridge et al. (11) showed that newborns can be
primed efficiently to alloantigen by injecting adult dendritic cells,
rather than total splenocytes. Using a murine leukemia virus, Sarzotti
et al. (12) elicited protective Th1-mediated antiviral responses by
titrating down the infective dose of the virus. Finally, Forsthuber et
al. (13) showed that injecting newborns with Ag in CFA, rather than
IFA, resulted in adult-like, Th1 responses. Together, these results
suggested that the neonatal T cell compartment was not inherently
biased toward Th2 responses; under the appropriate conditions,
adult-like Th1 responses could be achieved. However, all of the
experimental readouts in these studies were conducted weeks later,
after the animals had reached adulthood. As a result, the possibility
that the Th1 responses were actually mounted by T cells produced after
the neonatal period could not be eliminated. This is an important
point, since our in vitro studies (6) have shown that the capacity to
produce IL-2 and IFN- at adult levels requires a number of weeks
postbirth to develop.
The experiments reported in this work were designed to reveal the true
capacity of neonatal T cells in situ. We have examined the development
of primary immune responses in the neonate during the first week of
life. The production of IL-2, IL-4, and IFN- by lymph node T cells
was analyzed 6 days after immunization of 
24-h-old newborns with Ag
in PBS. We found that the lymph node response of newborns is very
similar to that of adults. Both Th1 and Th2 primary effector cell
populations were generated in the neonate, and the levels of cytokine
produced were comparable with those produced by adult cells. Thus,
during the first week of life, lymph node T cells are fully competent
to develop into Th1 effector cells in vivo. This capacity was already
fully mature as early as 1 day postbirth since neonatally thymectomized
mice also produced copious amounts of IFN- during a primary
response. Although neonatal and adult primary effector responses were
similar, they were not identical. Differences were observed in the
kinetics of cytokine production and in responses to adjuvant. Moreover,
even though a balanced Th1/Th2 primary response was observed, the
secondary responses (cytokines, IgG isotypes) of the same animals were
skewed toward Th2. Therefore, while neonates appear to be capable of
mounting adult-like primary Th1 responses, Th1-like cells are
apparently not well maintained in early life, and secondary responses
become dominated by the preferential persistence of the Th2
population.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
BALB/c mice, originally obtained from Charles River Laboratories
(Wilmington, MA), were bred and housed under barrier conditions in
Division of Veterinary Resources at University of Miami Medical School
(Miami, FL). Periodic screening showed the colony to be free of
commonly occurring infectious agents. Females from timed matings were
monitored closely at about day 20 of gestation (the average day of
birth in BALB/c mice), and the date of delivery was recorded. Birth day
was called day 0. Neonatal animals were defined as 24 h old.
Immunization
Adult (6–8 wk old) and newborn mice were immunized with 5
µg/g keyhole limpet hemocyanin
(KLH)3 (CalBiochem, San
Diego, CA) alone or DNP-conjugated KLH (DNP-KLH) (CalBiochem), as
indicated. The Ags were suspended in PBS for immunization, except for
the experiments in Figure 7
, in which the adjuvant CFA was also used.
Each mouse was injected in three sites, i.p. and s.c. between the
shoulder blades, and at the base of the tail. Adults received 100 µl
and babies 10 µl per site.
|
Pools of tissues from 
2 adults or 10 newborn animals were
used for the cell preparations.
Total lymph node or spleen cell suspensions
Total spleen cell suspensions were prepared and RBC were removed by incubation in hypotonic lysis buffer (0.15 M NH4Cl, 0.001 M KHCO3, and 0.1 mM EDTA). Mesenteric, inguinal, axillary, brachial, and cervical lymph nodes were mixed and used for total lymph node cell suspensions.
Enriched CD4+ and CD8+ cells
Total lymph node cell suspensions were passed over enrichment columns for mouse CD4+ or CD8+ cells (R&D Systems, Minneapolis, MN), precisely according to the manufacturer’s instructions. Enriched CD4+ suspensions were contaminated with <1% CD8+ cells; enriched CD8+ suspensions were contaminated with <1% CD4+ cells.
Adult splenic APC
Total spleen cells from adult animals were treated with anti-Thy-1 (42–21) plus complement, followed by treatment with 50 µg/ml mitomycin C, as described earlier (5, 14).
Thymectomies
Adult mice were anesthetized by i.p. injection of a mixture containing 0.2 mg and 1 mg per 10 g of body weight of, respectively, xylazine (Rugby Laboratories, Rockville Center, NY) and ketamine HCl (Fort Dodge Laboratories, Fort Dodge, IA). Neonatal mice were anesthetized by cooling in a reservoir of wet ice for approximately 1 min. A midline incision was made in the skin of the upper thoracic region to expose the sternum, and a second, longitudinal incision of the sternum was made to expose the tops of both thymic lobes. Both thymic lobes were then removed with a Pasteur pipette under a gentle vacuum. The chest was compressed to eliminate air in the thoracic cavity. The wounds in the adults were closed using surgical staples (Clay Adams, Parsippany, NJ), and the wounds in the newborns were sutured with Ethicon 6-0 sterile surgical braided silk (Roboz, Rockville, MD).
Cultures for cytokine production
A quantity amounting to 5 x 105 total lymph node cells was plated in 200 µl of culture medium (RPMI containing 10% FCS) and stimulated with the indicated concentrations of KLH. For cytokine production by subsets of T cells, 2 x 105 CD4+ or CD8+ cells (prepared as described above) were coplated in 200 µl culture medium with 4 x 105 adult splenic APC (as above) and stimulated with the indicated concentrations of KLH. Culture supernatants were harvested at the times indicated in the text.
Cytokine and serum ELISAs
Sandwich ELISA kits specific for mouse IL-2, IL-4, and IFN-
were purchased from Endogen (Cambridge, MA) and performed precisely per
the manufacturer’s instructions. Statistical analyses of the results
were performed using the paired Student’s t test.
p values 0.005 were considered significant.
Sera from individual animals were analyzed individually in ELISA assays specific for mouse IgG1 or IgG2a. Nunc Maxisorb plates were coated with 0.4 µg/well DNP-albumin (Calbiochem) overnight at r.t. The wells were then blocked with PBS containing 1% BSA for 1 h at r.t. The plates were washed with 50 mM Tris and 0.2% Tween-20, pH 7 (wash buffer), and 200 µl of the indicated serum dilutions was added to each well. After a second overnight incubation at r.t., the plates were washed with wash buffer, and 200 µl of a 1/2000 dilution of anti-mouse IgG1 horseradish peroxidase (Cappell, Durham, NC) or anti-mouse IgG2a horseradish peroxidase (Cappell) was added to each well and incubated for 2 h at r.t. The plates were washed again, and 100 µl of TMB substrate (Dako, Carpinteria, CA) were added to each well. Thirty minutes later, the reaction was stopped by the addition of 100 µl of 0.18 M sulfuric acid and the plates were read on an ELISA reader (OD450–OD550).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Several recent reports (11, 12, 13) have suggested that the newborn immune system is capable of mounting mature protective immune responses in vivo. However, in those experiments, the actual responses were not tested until weeks later, after the animal had grown into adulthood. Because of this experimental delay, the possibility that the mature responses may actually have been made by cells produced later in life could not be excluded. For these experiments, we wished to examine the responses of T cells present during the actual neonatal period. Although the neonatal spleen contains virtually undetectable proportions of T cells, the lymph nodes in neonates contain proportions of T cells similar to those found in adults (5). Therefore, we chose to compare the Ag-specific recall responses of lymph node T cells in adults and in neonates during the first week of life.
Newborns or adult animals were immunized both s.c. (between the
shoulder blades and at the base of the tail) and i.p. with 5 µg/g KLH
in PBS. Six to seven days later, lymph node cells were prepared and
restimulated in vitro with increasing amounts of KLH. Supernatants were
collected at the times indicated in the figure legends and assessed for
IL-2, IL-4, or IFN- content by specific ELISA. To guard against
variation from experiment to experiment in the absolute amounts of
cytokine produced, adults and neonates were compared directly within
each experiment. The production of all three cytokines by neonatal
lymph node effector cells was very similar to their production by adult
lymph node T cells (Fig. 1). This pattern
of cytokine production was not limited to the Ag KLH, but was also
observed for recall responses to OVA (not shown). These experiments
indicate that the lymph node T cells present in the first few days of
life are fully mature in their capacity to develop into Th1 and Th2
primary effector cells in vivo. Moreover, they demonstrate that
neonates and adults generate equivalent Th1 and Th2 primary effector
populations in vivo. Finally, these results indicate that the APC
population present in neonatal life is sufficiently mature to present
Ag efficiently and promote the development of Th effector cells in
situ.
|
). The two isotopes examined were IgG1
and IgG2a, whose production is promoted by, respectively, IL-4 and
IFN-. All animals immunized as adults or neonates produced
anti-DNP IgG1 Abs (Fig. 2, top), and the relative
levels of IgG1 produced by the neonates and adults were comparable. The
anti-DNP IgG2a responses were different; not all animals responded,
but the same proportion (roughly one-half) of adults and neonates made
anti-DNP IgG2a Abs. In addition, among the responders, animals
immunized as neonates produced the same levels (relative to the control
unimmunized littermates) of anti-DNP IgG2a Abs as did adults.
|
(above), argue against that idea. However, it could still be maintained
that the IFN- was actually being made by more developmentally mature
T cells that were produced after day 1, but before day 7, of life
(i.e., the time of analysis). To investigate this possibility,
24-h-old newborns or adult mice were thymectomized or sham
thymectomized and immunized with KLH. Six days later, lymph node cell
suspensions were restimulated with KLH, and supernatants were collected
for cytokine measurements (Fig. 3). There
was no significant difference in the amount of IL-4 produced by T cells
from sham vs thymectomized adult animals. However, IL-4 production by T
cells from thymectomized newborn mice was not detectable. In contrast,
IFN- production was affected similarly in newborns and adults with
thymectomy, resulting in a modest (
fourfold) increase. The IFN-
production by cells from the thymectomized neonates was remarkable
since there was such a severe reduction in T cell proportion in these
animals. While total lymph node cell suspensions from thymectomized and
sham-treated adults contained similar proportion of T cells, the
percentage of T cells was reduced up to 10-fold in suspensions from
thymectomized compared with sham neonates (sham newborns, 53 ±
0.5% CD4+, 16.4 ± 0.7% CD8+;
thymectomized newborns, 5.5 ± 0.5% CD4+, 1.3 ±
0.1% CD8+). Thus, the capacity to develop
IFN--secreting Th1 effector cells is fully mature on the first day
of life in mice, whereas the ability to develop Th2 responses appears
to require output by the thymus postbirth.
|
). In two separate experiments, the
major producer of IFN- among neonatal T cells was the
CD8+ population, whereas IL-4 was produced primarily by
CD4+ cells. This pattern was also observed for adults (not
shown). Therefore, mice 1 wk old contain CD4+ and
CD8+ populations capable of developing into adult-like
cytokine-secreting effector cells.
|
100-fold fewer T
cells (5, 11). Therefore, for comparative responses with immunized
adults, it is not immediately obvious how to adjust the dose of
immunogen for neonates. To address this issue, we immunized newborns
with a 50-fold range and adults with a 25-fold range of KLH amounts.
Six days later, IFN- and IL-4 production by lymph node T cells in
response to restimulation in vitro were assessed (Fig. 5). Over this broad range in immunogen
dose, there did not appear to be any single dose that preferentially
stimulated Th1 or Th2 cytokines. In general, if a dose resulted in
increased (or decreased) IFN-, there would also be increased (or
decreased) IL-4 production. This pattern was observed for both neonates
and adults. Therefore, at least when immunogens are delivered in PBS,
neonates and adults produce both Th1 and Th2 effector responses over a
wide range of immunogen dose.
|
Although neonates and adults showed many similarities in their
development of Th1 and Th2 primary effector populations, they were not
identical. The first difference was revealed by experiments to chart
the kinetics of cytokine production by neonatal vs adult T cells.
Newborns 24 h old and adult animals were immunized with KLH, and
lymph node cells were restimulated with KLH in vitro 6 days later.
Supernatants were harvested at 24, 48, and 72 h of culture, and
IL-2, IL-4, and IFN- ELISAs were performed (Fig. 6). Major differences were seen in the
kinetics of production of all three cytokines by neonates and adults.
Neonates produced copious amounts of IL-2 24 h after stimulation,
but culture supernatants no longer contained detectable IL-2 by 48
h. In contrast, adult cultures did not have detectable IL-2 at 24
h, but, by 48 h, large amounts of IL-2 were evident. Similar
kinetic differences were seen for IL-4 and IFN-, except at later
time points. By 48 h of activation, neonates produced high levels
of both of these cytokines. In contrast, adults produced no detectable
IL-4 and >fivefold less (p = 0.001) IFN-
than neonates at this time point. Adult cells did not make large
quantities of IL-4 or IFN- until 72 h of stimulation. Thus,
cytokine production by cells from neonatal animals proceeded with more
rapid kinetics than that by adult cells; neonatal T cells produced high
levels of Th1 and Th2 cytokines up to 24 h earlier than adult T
cells following restimulation in vitro.
|
24 h old and adult animals were immunized with KLH either in
PBS or CFA. Six days later, lymph node cells were restimulated with
different concentrations of KLH, and supernatants were harvested for
ELISA analyses (Fig. 7
). Unlike that
observed with immunization using PBS as the vehicle, IL-4 production by
either adults or neonates immunized with KLH in CFA was undetectable.
Adults immunized using CFA showed a modest increase (not statistically
significant) in IL-2 secretion. In contrast, adult IFN- production
was enhanced 10-fold (p < 0.004) when
immunization was performed with CFA. The effects of CFA on IL-2 and
IFN- production by neonates were strikingly different. IL-2
production was reduced severely (p < 0.004),
while IFN- was not enhanced (p > 0.01).
Only single time points are shown, but supernatants from 24 to 72
h were examined to ensure that differences between CFA and PBS were not
simply due to differences in the kinetics of cytokine production.
Therefore, unlike in adults, CFA does not act to enhance the
development of primary Th1 effector cells during early neonatal
life. Although neonates mount balanced Th1/Th2 primary responses, mice immunized at birth are skewed toward Th2 secondary responses
It has been reported recently (9, 10) that mice immunized
with Ag in adjuvant at birth become primed to develop highly skewed Th2
secondary responses. Since we had seen a balanced Th1/Th2 primary
response using PBS as the vehicle, we wished to know whether our mice
were nonetheless biased toward Th2 secondary responses. Newborns 24 h
old or adult animals were immunized with KLH, as previously described.
Four weeks later, the mice were reimmunized with 5 µg/g KLH in PBS.
Eight days later, serum and lymph node and spleen cell suspensions were
prepared from the mice. Spleen and lymph node cell suspensions were
restimulated separately with KLH, and supernatants were harvested for
ELISA. In adults, lymph node cells produced little cytokine; the vast
majority of cells producing either IL-4 or IFN- were found in the
spleen (Fig. 8). Low level IL-4 and
IFN- production in the adult lymph node cultures was not due to a
general inability of the cells to produce cytokine since they
simultaneously produced 1) large amounts of IL-2 in response to KLH
stimulation, and 2) high levels of IFN- in response to anti-CD3
stimulation (not shown). In contrast, both lymph node and spleen cells
from animals first immunized as newborns produced IL-4 and IFN-.
Lymph node cells from these animals made significantly
(p < 0.001) more IL-4 than lymph node cells
from immunized adults, whereas IFN- production was significantly
(p = 0.005) decreased among splenocytes
compared with spleen cells from immunized adults. Moreover, when the
total cytokine produced (sum of lymph node and splenic responses) is
accounted for, animals immunized at birth produced threefold less
IFN- and threefold more IL-4 than did adults. These in vitro
cytokine profiles are representative of the cytokines available in vivo
since there is a clear bias toward IgG1 production by mice immunized as
neonates, but not by adults (Fig. 9).
Therefore, while the primary Th1/Th2 profiles produced by neonates and
adults are very similar, neonates are clearly biased toward Th2
secondary responses.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Thus, the T cell population is sufficiently mature within the
first week of life to develop balanced Th1/Th2 primary effector
populations similar to those produced by adults. Because the
development of Th cells requires APC, this result also suggests that
the APC population in newborns is functionally mature. Although the
primary cytokine profiles of neonatal and adult animals were very
similar, other aspects of the immune responses showed major
differences. Upon in vitro restimulation, primary effector cells from
neonates produced IL-2, IL-4, and IFN- up to 24 h earlier than
did primary adult effectors. While adult IFN- was enhanced 10-fold
by CFA, adjuvant had little to no effect on the generation of primary
IFN--secreting cells in the neonate. Finally, despite balanced
Th1/Th2 primary responses, the secondary responses of mice immunized as
neonates were skewed toward the Th2 pathway. These results demonstrate
that neonates are developmentally mature in their capacity to mount
primary, adult-like Th1/Th2 responses in vivo. However, neonates are
developmentally immature in their kinetics of cytokine production,
responsiveness to adjuvant, and the maintenance and/or generation of
Th1 secondary responses.
One of the major differences seen between newborn and adult
primary effectors was in the kinetics of cytokine production. The
production of maximal amounts of all three cytokines, IL-2, IL-4, and
IFN-, by neonatal T cells occurred 24 h earlier than their
production by adult T cells. The mechanism(s) underlying more rapid
response kinetics is unknown. However, the rapid cytokine production by
neonatal effector cells may be just one reflection of a developmental
state in which the T cells are poised to respond quickly. In support of
this idea, we have also found that polyclonally activated, naive
newborn (4-day-old) T cells enter the cell cycle with more rapid
kinetics than do adult T cells (not shown). In addition to starting
earlier, the responses of neonatal T cells also end earlier. For
example, while IL-2 is present in cultures of neonatal T cells at
24 h, it is no longer detectable at 48 h, presumably because
it has been utilized by the cells. Adult cultures, on the other hand,
contain copious amounts of IL-2 at 48 h of activation. Similarly,
polyclonally activated, naive neonatal T cells appear to enter the cell
cycle earlier and subsequently revert to cultures containing largely
G0-G1 cells 1 full day earlier than adult
T cells (unpublished observation). A possible consequence of these
rapid kinetics is that the overall immune response may be temporally
limited in neonates. It is tempting to speculate that developmental
regulation of the kinetics of immune responsiveness contributes to the
relatively immunodeficient state of newborns.
A second major difference between the primary responses of
neonates and adults was seen when Ag was introduced in CFA. In adult
animals, CFA markedly enhanced Th1 responses. IFN- production was
enhanced 10-fold over that produced when Ag was delivered in PBS. In
contrast, IFN- was largely unaffected in neonates immunized with
CFA. This contrasts with reports (9, 13) by others that different
adjuvants could elicit adult-level Th1 responses from neonates. Perhaps
one major difference between our system and those of others is that we
have analyzed cytokine production during the first week of life,
whereas others allowed the neonates to age 2 wk before analysis. It
is possible that the adult-like Th1 responses observed in the latter
systems actually resulted from cells produced after the immediate
neonatal period. Nonetheless, these results illustrate that the choice
of adjuvant (or lack thereof) is critical in determining the type of Th
response generated in the neonate. Moreover, our results clearly
demonstrate that one cannot predict a newborn response to a particular
adjuvant (e.g., CFA) from the type of response elicited in adults. Due
to the strong relevance to vaccine development, it will be important to
more clearly define the effects of different adjuvants on both the
primary and secondary responses of neonates.
Since neonates develop fully mature primary Th1 effector populations, the question that arises is why are they relatively deficient in producing Th1 responses to secondary immunization? There are at least two possible explanations for this phenomenon. First, Th1 cells capable of responding to secondary stimulation may be present, but unable to respond, i.e., they may be anergized. This possibility seems unlikely because endogenous IL-2, a cytokine that usually reverses nonresponsiveness, is present at similar levels in cultures prepared from twice immunized adults and neonates (not shown). The second possibility is that the Th1 cells generated initially may show poor survival, and hence, their numbers would be limiting in a secondary response. There are in vitro data that make this possibility appealing. Several years ago, we showed (14) that approximately one-half of the lymph node T cells from 4-day-old animals undergo apoptosis in response to a single round of stimulation with anti-CD3 Ab. It could be proposed that apoptosis also occurs in vivo following the initial effector phase, and the major population affected is the Th1 cell type. This is an exciting possibility because it suggests a mechanism that could account for tolerance induction during the neonatal period.
In addition to showing skewed Th2 secondary responses, neonates
differed from adults in the organs contributing to secondary responses.
In newborns, both lymph node and spleen cells made IL-4 and IFN-. In
contrast, production of both cytokines in the adult was largely
confined to the spleen. This was not due to a generalized inactivity of
the adult lymph node cells since the same cells produced large amounts
of IL-2 in response to the Ag and high levels of IFN- in response to
anti-CD3 stimulation (not shown). It is not clear how this arises,
but it may be that recirculation of primed/memory cells is different in
early life and adulthood. For example, primed/memory cells may not
recirculate efficiently from the lymph nodes to the spleen in newborns
and juvenile mice. In that case, relatively more activity would be
retained in the lymph nodes. This could have important implications for
vaccine responsiveness, i.e., an immunization route that reaches both
the lymph nodes and spleen may be more important in early
life.
The experiments performed with euthymic mice suggest that the
capacity to develop adult-like Th1 and Th2 primary effector responses
is mature within the first week of life. To determine whether this was
a true property of the cells already resident on day 1 of life, we
similarly examined thymectomized newborns. Total lymph node cells from
thymectomized mice produced IFN- at levels similar to those produced
by cells from sham-thymectomized newborns. In contrast, IL-4 production
was greatly reduced in thymectomized newborns. In the thymectomized
mice, the proportion of T cells in total lymph node suspensions was
reduced approximately 10-fold. The poor IL-4 production may have
resulted from the limited numbers of T cells present. However, it is
clear that there were sufficient numbers of cells present for the
production of copious amounts of IFN-. Thus, an alternative
explanation for poor IL-4 production is that cells capable of
developing into Th2 effectors may not be produced efficiently in the
thymus until after the first day of life. We are currently conducting
experiments to test this hypothesis.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. B. Adkins, Department of Pathology R-5, University of Miami Medical School, P.O. Box 016960, Miami, FL 33103.
3 Abbreviations used in this paper: KLH, keyhole limpet hemocyanin; r.t., room temperature.
Received for publication August 14, 1997. Accepted for publication December 31, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production by murine peripheral T lymphocytes. J. Immunol. 151:6117.
ß-transgenic model. J. Exp. Med. 182:1579.This article has been cited by other articles:
|
|
 |
|
  Z. Szepfalusi The Maturation of the Fetal and Neonatal Immune System J. Nutr., September 1, 2008; 138(9): 1773S - 1781S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Opiela, R. B. Levy, and B. Adkins Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens Blood, August 15, 2008; 112(4): 1530 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rose, M. Lichtenheld, M. R. Foote, and B. Adkins Murine Neonatal CD4+ Cells Are Poised for Rapid Th2 Effector-Like Function J. Immunol., March 1, 2007; 178(5): 2667 - 2678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Caprio-Young, J. J. Bell, H.-H. Lee, J. Ellis, D. Nast, G. Sayler, B. Min, and H. Zaghouani Neonatally Primed Lymph Node, but Not Splenic T Cells, Display a Gly-Gly Motif within the TCR {beta}-Chain Complementarity-Determining Region 3 That Controls Affinity and May Affect Lymphoid Organ Retention J. Immunol., January 1, 2006; 176(1): 357 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rowe, S. T. Yerkovich, P. Richmond, D. Suriyaarachchi, E. Fisher, L. Feddema, R. Loh, P. D. Sly, and P. G. Holt Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children Infect. Immun., December 1, 2005; 73(12): 8130 - 8135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Patton, T. C. McGuire, M. T. Hines, R. H. Mealey, and S. A. Hines Rhodococcus equi-Specific Cytotoxic T Lymphocytes in Immune Horses and Development in Asymptomatic Foals Infect. Immun., April 1, 2005; 73(4): 2083 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Empey, M. Hollifield, K. Schuer, F. Gigliotti, and B. A. Garvy Passive Immunization of Neonatal Mice against Pneumocystis carinii f. sp. muris Enhances Control of Infection without Stimulating Inflammation Infect. Immun., November 1, 2004; 72(11): 6211 - 6220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chang-Rodriguez, R. Ecker, G. Stingl, and A. Elbe-Burger Autocrine IL-10 partially prevents differentiation of neonatal dendritic epidermal leukocytes into Langerhans cells J. Leukoc. Biol., September 1, 2004; 76(3): 657 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. T. Tobagus, W. R. Thomas, and P. G. Holt Adjuvant Costimulation during Secondary Antigen Challenge Directs Qualitative Aspects of Oral Tolerance Induction, Particularly during the Neonatal Period J. Immunol., February 15, 2004; 172(4): 2274 - 2285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Koyanagi, K.'i. Imanishi, Y. Arimura, H. Kato, J. Yagi, and T. Uchiyama Immunologic immaturity, but high IL-4 productivity, of murine neonatal thymic CD4 single-positive T cells in the last stage of maturation Int. Immunol., February 1, 2004; 16(2): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dakic, Q.-x. Shao, A. D'Amico, M. O'Keeffe, W.-f. Chen, K. Shortman, and L. Wu Development of the Dendritic Cell System during Mouse Ontogeny J. Immunol., January 15, 2004; 172(2): 1018 - 1027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Adams, N. Nagy, F. Paulart, M.-L. Vanderhaeghen, M. Goldman, and V. Flamand CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization J. Immunol., November 15, 2003; 171(10): 5071 - 5076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Adkins Peripheral CD4+ Lymphocytes Derived from Fetal versus Adult Thymic Precursors Differ Phenotypically and Functionally J. Immunol., November 15, 2003; 171(10): 5157 - 5164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Bell, B. Min, R. K. Gregg, H.-H. Lee, and H. Zaghouani Break of Neonatal Th1 Tolerance and Exacerbation of Experimental Allergic Encephalomyelitis by Interference with B7 Costimulation J. Immunol., August 15, 2003; 171(4): 1801 - 1808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Adkins, T. Williamson, P. Guevara, and Y. Bu Murine Neonatal Lymphocytes Show Rapid Early Cell Cycle Entry and Cell Division J. Immunol., May 1, 2003; 170(9): 4548 - 4556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Eisenberg, S. J. Czinn, C. A. Garhart, R. W. Redline, W. C. Bartholomae, J. M. Gottwein, J. G. Nedrud, S. E. Emancipator, B. B. Boehm, P. V. Lehmann, et al. Protective Efficacy of Anti-Helicobacterpylori Immunity following Systemic Immunization of Neonatal Mice Infect. Immun., April 1, 2003; 71(4): 1820 - 1827. [Abstract] [Full Text]
|
|
|
|
|
|
J. W. Upham, P. T. Lee, B. J. Holt, T. Heaton, S. L. Prescott, M. J. Sharp, P. D. Sly, and P. G. Holt Development of Interleukin-12-Producing Capacity throughout Childhood Infect. Immun., December 1, 2002; 70(12): 6583 - 6588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Adkins, Y. Bu, and P. Guevara Murine Neonatal CD4+ Lymph Node Cells Are Highly Deficient in the Development of Antigen-Specific Th1 Function in Adoptive Adult Hosts J. Immunol., November 1, 2002; 169(9): 4998 - 5004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dadaglio, C.-M. Sun, R. Lo-Man, C. A. Siegrist, and C. Leclerc Efficient In Vivo Priming of Specific Cytotoxic T Cell Responses by Neonatal Dendritic Cells J. Immunol., March 1, 2002; 168(5): 2219 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
= unimmunized control animals; • = immunized animals. All
mice immunized as neonates (n = 8) or adults
(n = 4) produced anti-DNP IgG1 Abs. Two
representative immunized animals of each age group are shown. All
immunized adults produced high levels of anti-DNP IgG2a Abs, and
two representative individual animals are shown. Four of the eight mice
immunized as neonates produced intermediate levels of anti-DNP
IgG2a Abs, and the other four produced low levels. One immunized
neonate from each of these two response patterns is shown.