Allergy 2000: 55: 688±697 Copyright # Munksgaard 2000

Printed in UK. All rights reserved

ALLERGY
ISSN 0105-4538

Allergy Review Series VI: The immunology of fetuses and infants

The development of the immune system during pregnancy

and early life

P. G. Holt
TVW Telethon Institute for Child Health Research,
Perth, Australia and Department of Microbiology,
University of Western Australia, Perth, Australia

C. A. Jones
University of Southampton, Southampton, UK

Professor P. G. Holt
Division of Cell Biology
TVW Telethon Institute for Child Health Research
PO Box 855
West Perth WA 6872
Australia

Accepted for publication 3 February 2000

It is a common misconception that the newborn is (>37 weeks of gestation). Due to ethical limitations,
immunologically naive. However, neonatal human few studies have been conducted on fetal lymphoid
T cells proliferate in response to an array of antigens, tissues or blood at earlier times in gestation. This review
including allergens (1±4), autoantigens (5), and parasite contrasts the published data obtained from studies on
antigens (6, 7). The ability to detect antigen-speci®c IgE fetal and newborn peripheral blood mononuclear cells
in umbilical cord blood collected at birth also indicates with the more limited information available on samples
that neonatal T and B cells have mounted an antigen- from infants and young children. In addition, the
speci®c response (8±10). Likewise, newborns of mothers rami®cations of these ®ndings are discussed in relation
who are vaccinated with tetanus toxoid during preg- to the pathogenesis of allergic disease.
nancy have speci®c antibody of the IgM class in their
serum, although no evidence of class switch before their
own vaccination (11). The offspring of mothers infected Development of the fetal immune system
by Ascaris during the pregnancy (12) also exhibit As in all mammals, the ®rst stage of human fetal haemo-
speci®c reactivity to this parasite at birth. poiesis occurs in the mesoderm of the yolk sac and
Nevertheless, fetal and newborn mammals have the extraembryonic mesenchymal tissue. Pluripotent
limited ability to mount immune responses in both erythroid and granulomacrophage progenitors can be
quantitative and qualitative terms, relative to older age detected in the yolk sac of human embryos at 3±4 weeks
groups. This defect could reside in any combination of of gestation. These primitive cells can then be detected in
functions associated with mounting effective host the circulation from 4 weeks of gestation as they migrate
defence, but, in some circumstances, the magnitude of to the liver, which becomes the major site of haemopoi-
the defect has been overestimated as a result of the esis at 5±6 weeks of gestation. From 5±10 weeks, the liver
methodology chosen to examine immune function. undergoes a dramatic increase in size as the number of
Most investigations of the functionality of the human nucleated cells rises. These early progenitors are
fetal immune system have relied on the use of umbilical proliferating but undergoing very little differentiation,
cord blood collected at birth after a full-term pregnancy although a discrete granulocyte/macrophage population

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 Fetal immune system

emerges at this time. The thymus and spleen are seeded passes through the left umbilical vein and therefore
from the liver and stem cells are detectable in the bone comes directly from the placenta, providing a rich
marrow at 11±12 weeks of gestation (13). Hepatic nutrient supply to these cells (17). HLA-DR+
haemopoiesis declines in the third trimester and ceases Langerhans cells are detectable in the skin by 6±7
soon after birth. weeks of gestation. The density of these cells at days
The culture of fetal blood collected by fetoscopy at 50±100 of gestation is similar, but the cells are smaller
12±19 weeks of gestation yields high levels of both in the earlier gestational samples, as well as less
erythroid and granulocytic/monocytic progenitor cells ± dendritic and phenotypically heterogeneous. Thus,
monocytes comprising 42±68%, neutrophils 27±41%, Langerhans cells migrate into the epidermis during
and eosinophils 5±30% (14). Despite this high number the ®rst trimester and resemble the adult phenotype by
of granulocyte progenitors in the circulation at this the second trimester (18). There are MHC class II-
time, granulocytes are not formed in large numbers in positive cells in the lamina propria of the fetal gut as
fetuses until after birth, neutrophils being actually the early as 11 weeks of gestation, but the cell type
last population to appear in the blood during fetal life remains unidenti®ed (19).
(15). The only monocyte/macrophage populations that
What follows is a summary of the development of the have been functionally assessed are those in the
cell populations that allergologists are familiar with circulation collected as umbilical cord blood at term
from their role in the allergic response. When they were or, less frequently, preterm delivery. Term cord-blood
known, the functional properties of these cells have also monocytes have decreased production of a number of
been considered. cytokines, including TNF-a (20), in comparison to the
adult. Although cord-blood mononuclear cells can
phagocytose at a level comparable to the adult,
chemotaxis is reduced (21). Assessment of allogeneic
Macrophages and dendritic cells responses by cord-blood mononuclear cells to adult
Macrophages, dendritic cells, and B cells, which are peripheral blood leukocytes (22) has con®rmed that
discussed later, have a central role in the generation of the antigen-presenting function of cord-blood mono-
an antigen-speci®c immune response, as they take up, nuclear cells is suf®ciently developed to mediate a
process, and present antigens to T cells. Although response comparable to the adult. The status of the
dendritic cells are considered professional antigen- neonatal monocyte has also been implicated in
presenting cells because they can prime naive T cells, determining some aspects of T-cell function, as this
very little is known about them in the fetal period; cell type has a role in mediating impaired IFN-c
therefore, they will be discussed with monocyte/ production by neonatal T cells (23, 24).
macrophages, which are the ®rst cell type to appear The one study of cord-blood dendritic cells suggests
in the fetal circulation (15). that they express relatively poor accessory function
There are two populations of cells with a dendritic/ (25). Umbilical cord-blood dendritic cells in this study
macrophage structure in the yolk sac and mesenchyme had lower levels of ICAM-1 and MHC classes I and II
at 4±6 weeks of age. Cells with this appearance are than peripheral blood dendritic cells from adults.
also evident in the prehaematopoietic liver at 5 weeks Cord-blood dendritic cells were poor stimulators of
of gestation. The major population of yolk sac mixed lymphocyte reactions irrespective of whether
macrophages is MHC class II-negative, and there is cord or adult MNC or T cells were used as the
a minor population that is MHC class II-positive (16). responders. In contrast, cord-blood T cells and
MHC class II-negative cells appear in the thymic mononuclear cells responded normally to allogeneic
cortex, in the marginal zones of lymph nodes, in the adult dendritic cells.
splenic red pulp, and in the midst of erythopoietic
activity in the bone marrow. A few MHC class II-
positive cells are seen in the liver at 7±8 weeks of T cells
gestation, the lymph nodes at 11±13 weeks of Putative prothymocytes can be identi®ed in the fetal
gestation, and the T-cell areas of the developing liver from 7 weeks of gestation as highly proliferative
thymic medulla by 16 weeks of gestation, whereas cells that are positive for CD7, CD45, and cytoplasmic
thymic epithelium expresses class II at 8±9 weeks (16). CD3, but do not express membrane CD3, TCR b
MHC class II-positive cells also occur in the skin, chain, or TdT (terminal deoxynucleotidyl transferase,
gastrointestinal tract, and hepatic systems. The which is involved in diversi®cation of the DJ region of
number of hepatic sinusoidal macrophages (Kupffer Ig heavy chain and the T-cell receptor [TCR]).
cells) is low in early gestation (17 weeks was the Membrane CD3 is evident after week 10 of gestation,
earliest time point examined) but increases to nearly at which time the cells are less proliferative (26, 27).
adult levels in the neonatal period. By 6 weeks of CD7+ T-cell precursors from the fetal liver seed the
intrauterine development, the blood ¯ow to the liver thymus at 8±9 weeks of gestation; 60% of these are

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Holt and Jones

CD2+ (cytoplasmic), only 4% are CD3+ (cytoplas- that have leaked from the thymus, and are thus
mic), and none are TCR d or b positive. From 9.5 an immature population rather than a memory
weeks to birth, TCR b+ cells increase to form over population?
90% of the CD7+ population (28). CD7 is an early The fetal gastrointestinal tract may be a site of
T-lineage marker not found on myeloid or erythroid extrathymic differentiation of T cells, as has been
lineages and is a good marker of T cells that have not demonstrated in the mouse (34). Human fetal
yet expressed markers of later T-cell subsets such as intestinal mucosa has T cells detectable in the
CD3, 4, or 8. Cells from SCID-human thymus/liver or lamina propria and epithelium from 12±14 weeks of
human T cells from SCID-human peripheral blood are gestation (35). T cells in fetal ileum epithelium are
functionally competent. They are similar to fetal mostly CD8+, and many of these express CD8aa.
thymocytes or adult T cells, respectively (29, 30). Almost half of the CD8+ cells in the lamina propria
From 18±24 weeks of gestation, the mesenteric are also CD8aa, but in the Peyer's patches, when
lymph nodes have a high percentage of CD45RA+ present, CD8ab cells predominate (36). Studies in mice
T cells but very few B cells or monocytes. The fetal indicate that CD8aa cells may be thymus-independent
spleen at this time has equal numbers of T cells, B and develop in the gut.
cells, and monocytes/macrophages (31). Lymph-node A substantial proportion of lamina propria lym-
and thymus T cells at these gestational ages do not phocytes express CD7 in the absence of CD3 and are
proliferate in response to the mitogen PHA or upon proliferating, as indicated by Ki67 expression. There is
anti-CD3 stimulation, although expression of CD69, no overlap between the gut and the blood in
an activation marker, does increase. Proliferation is rearranged TCR b transcripts; therefore, the gut
observed on the addition of IL-2. In contrast, splenic T cells are unlikely to be derived from blood (37).
T cells do proliferate to PHA and anti-CD3. T cells As Peyer's patches are not present until 16±19 weeks
from fetal spleen have adult levels of CD3, CD4, and of gestation, the T cells populating the gut prior to this
CD8, and also expressed CD2 and CD11a. Thus, the time are unlikely to be T cells recirculating from the
spleen is considered already fully immunocompetent Peyer's patches to the lamina propria, as occurs in
by 18 weeks of gestation, having suf®cient accessory adulthood. Furthermore, T cells in the fetal intestine
cells to ensure T-cell activation, whereas the mesenteric express activation markers (HLA-DR, CD25, CD69,
lymph nodes are de®cient in accessory cells numeri- and low CD62L), and the majority express CD45RO
cally or functionally. The ability to upregulate CD69 (37). However, this population may also re¯ect thymus
by fetal T cells upon stimulation with anti-CD3 or leakage, as thymus development is complete by the
PHA was comparable to the adult, whereas the time these cells appear in the gut.
response of fetal T cells to allogeneic antigen- Given the recent resurgence of interest in c/d T cells
presenting cells was much greater than the adult. in allergic disease (38), especially asthma, when and
The latter observation has been postulated to re¯ect where does this subpopulation of T cells develop
the limited diversity of the TCR a/b repertoire of fetal during fetal life? Rearranged TCR d genes are ®rst
T cells. seen in the liver and primitive gut between 6 and 9
There are few memory T cells (CD45RO+) in the weeks of gestation prior to being detectable in the
blood and spleen of the newborn, whereas half the thymus (39). The thymic and gut c/d T-cell repertoires
T cells in adult tissues have this phenotype. overlap early in development but diverge and become
Surprisingly, CD45RO+/RA± T cells are relatively nonoverlapping during the second trimester (40),
abundant in the spleen and blood from premature whereas the c/d T-cell population in the fetal liver is
births, about 25% and 10%, respectively, with both distinct from the thymus, and the liver may be a site of
CD4 and CD8 subpopulations contributing. The c/d T-cell development in man. In the liver at 20±22
CD4+/CD45RO+ population frequently expressed weeks of gestation, 63% of CD3+ cells are TCR a/b
CD25 and could proliferate in response to IL-2, but and 32% are TCR c/d. Peculiarly, a subpopulation of
not anti-CD2 or anti-CD3 (32). The investigators these liver c/d T cells has a CD4+ phenotype.
postulated that these cells were an embryonic popula- CD3+ T cells are detectable in the fetal circulation
tion of autoreactive T-cell clones with anergic at about 15±16 weeks of gestation, at which time they
characteristics. Leakage of self-reactive T cells to the also express CD2 and CD5 (41). Proliferation in
periphery before negative selection has occurred has response to PHA is ®rst seen at 17 weeks of gestation
been postulated to be greater during fetal life. (42). How early do antigen-speci®c responses occur?
CD45RO is considered a marker of memory T cells; Umbilical cord mononuclear cells collected at birth at
however, a switch from CD45RO to CD45RA occurs full term exhibit antigen-speci®c reactivity to allergens,
as the ®nal step of maturation in the thymus (33). including those of house-dust mite and cow's milk
Therefore, do these CD45RO+ cells in the fetal liver, (1±4); parasite antigens such as those of Plasmodium
spleen, and circulation re¯ect very immature T cells spp. (7) and Schistosoma spp. (6); and autoantigens,

690
 Fetal immune system

including myelin basic protein (5). Most of these weeks of gestation. CD24 expression precedes m-chain
studies have used proliferation assays, but antigen- expression and is retained throughout differentiation
speci®c cytokine production has also been observed. into adulthood. Liver B cells also express CD20 but
Antigen-speci®c reactivity at earlier time points has are negative for CD21 and CD22 (52).
been poorly studied. The study already cited (32) Diffusely distributed B cells detectable in the lymph
examined T-cell phenotypes in early gestation but did nodes from 16±17 weeks and spleen at 16±21 weeks are
not investigate antigen-speci®c reactivity by these cells. strongly IgM+ (50, 51). Primary nodules develop
Another study investigating allergen-speci®c prolifera- around the follicular dendritic cells of the lymph nodes
tive responses demonstrated antigen-speci®c reactivity from 17 weeks of gestation, and contain a virtually
at 23 weeks of gestation (43). Although this is an pure B-cell population. Germinal centre B cells are
interesting observation, much more information is absent in the fetal lymph nodes, probably re¯ecting a
required about the phenotype of cells making such lack of antigen. B cells are abundant in the bone
responses, and the genuine speci®city of such marrow at 16±20 weeks of gestation. The proportion
responses requires con®rmation. This applies to all of immature B cells in the bone marrow decreases with
studies of antigen-speci®c reactivity at birth, given that age, and cells expressing maturity markers increase. B
most babies demonstrate reactivity to one or more cells in the spleen are diffusely distributed at 22 weeks,
antigens. and then form primary nodules around 24 weeks; this
One of the frequently observed properties of is later than seen in lymph nodes.
neonatal T cells is their poor cytokine production in B cells emerge into the peripheral circulation at 12
comparison to the adult (44, 45), particularly in weeks of gestation, and they are positive for CD19,
relation to Th1 cytokines. The underlying mechanisms CD20, CD21, CD22, HLA-DR, IgM, and IgD (52).
that account for this de®ciency are incompletely The percentage of CD5+ B cells (B-1 B cells) is higher
understood, but appear to derive in part from the in the fetal circulation than the adult, and declines
secretory functions of the placenta ([46] further with increasing gestational age, yet even at birth most
discussion below). The relatively poor capacity of cord-blood B cells are CD5+ (B-1 B cells), in contrast
neonatal T cells to produce cytokines is thought to to the adult, where few peripheral blood B cells
contribute to the impaired responses of other neonatal express this molecule (52, 53). CD5+ B cells are
cell populations that rely on these factors for their largely T-independent, and CD5+ B cells produce
functions. For example, poor IFN-c production could polyreactive antibodies which may have a role in the
help to reduce cellular cytotoxicity by NK cells (47), primary immune response and be very useful in
and reduced IL-4 has a role in reduced IgE production the ®rst line of defence, a necessary function in the
by neonatal B cells (48). newborn.

B cells Immunoglobulin production

Pro- (CD24+/surface IgM-negative) and pre-B cells Early IgG and IgM synthesis occurs primarily in the
(cytoplasmic IgM+/surface IgM-negative) can be spleen, large amounts of both being produced by the
detected in the fetal liver and omentum (a long fold spleen as early as 10 weeks of gestation, although
of peritoneal membrane which hangs down within the levels are maximal at 17±18 weeks of gestation. Serum
abdominal cavity in front of the bowels, and which is IgG levels slowly increase between 5.5 and 22 weeks,
considered part of the lymphoid system because it there is a greater increase to 26 weeks, and then there
contains loose unorganized lymphoid aggregates), but is a dramatic increase to birth. IgG of a haplotype
not the spleen, as early as 8 weeks of gestation. The distinct from the mother can be detected in the fetal
percentage of pre-B cells in the fetal omentum and circulation as early as 17 weeks of gestation as well as
liver is similar over 8±12 weeks gestation, but the at birth, although most of the IgG is of maternal
percentage of these cells decreases during weeks 13±23 origin (54). IgG traverses the placenta throughout
in the omentum, remaining the same in the liver (49). gestation with a marked upregulation in the transfer
Thus, B-cell development in the omentum is transi- rate occurring from 20 weeks, and this upregulation is
tory. B cells become detectable in the spleen at 13±23 maximal from 32 weeks of gestation (55, 56). IgE
weeks of gestation, and CD5+ B cells can be found in synthesis was observed at 11 weeks of gestation in fetal
the human peritoneal cavity and pleural cavity at 15 liver and lung, and by 21 weeks in the spleen (57).
weeks of gestation (50). Despite this early burst of production in fetal life,
The liver is an important site of B-cell differentia- the production of Ig isotypes at birth is impaired.
tion in mammals (51). At 8 weeks of gestation, liver Neonates have very low serum IgM and even lower
pre-B cells express the cytoplasmic m chain, and IgA and IgE levels, and the IgG present is essentially
surface IgM is expressed on liver B cells by 10±12 of maternal origin. Polyclonal activators such as
weeks, with surface IgD being detectable from 13 pokeweed mitogen fail to switch neonatal B cells to

691
Holt and Jones

IgA and IgG production. The neonatal immune levels increasing rapidly to adult levels by 1 week
system responds to a restricted array of antigens postnatally. There is some con¯ict in the literature
producing largely IgM of low af®nity. Surface IgM about HLA-DR expression by the intestinal epithe-
and CD79 (signal transducer for membrane Ig and lium, but there is clearly a population of MHC class
necessary for all IgM functions) are elevated on cord- II-positive cells in the lamina propria from 11 weeks of
blood B cells compared to the adult, but cord and gestation (19), and, as mentioned above, T cells are
adult B cells express similar levels of CD19, 21, 22, found at this site from 12±14 weeks of gestation (37).
and 81, although CD32 is lower on cord B cells (58). From the second postnatal week, intense expression of
Neonatal B cells are also mature in their capacity to epithelial HLA-DR, secretory component, and IgA is
switch to IgE-producing cells if they are given seen, again re¯ecting modulation by environmental
exogenous IL-4, albeit they require levels of IL-4 factors (65).
higher than that required by adult B cells to switch to Immune responses at mucosal surfaces have an
IgE production (48). Thus, the minimal production of important role in the development of allergic responses
IgE is not due to the immaturity of the B cells but to and disease. Although there are very few studies of
the lack of IL-4 produced by fetal cells, i.e., to the these sites during intrauterine development, it is clear
immature helper T-cell function. Another molecule that both the skin and gastrointestinal tract are
important in directing B cells to switch to IgE relatively immunologically mature, at least structu-
production is CD40 via interaction with its ligand rally, prior to birth. In contrast, the airways show little
(CD40L) on T cells. CD40L expression is not evidence of population by haematopoietic cells prior
inducible on CD3+ cells from newborn samples to birth, and an in¯ux is seen during the ®rst week
activated with many (59±61), but not all (62), stimuli; postnatally (66). This developmental delay in the
however, it can be readily upregulated to levels airways may help to explain why allergic disease is ®rst
comparable to the adult at 19±28 weeks of gestation, manifest in the gut and skin while the clinical
the levels declining toward full term (59). symptoms of airways in¯ammation appear later in
As IgE has a central role in the allergic response, it infancy/childhood.
is worthwhile noting that despite the low levels of total
IgE detectable in the circulation, speci®c IgE (either
allergen or parasite) is detectable in cord plasma from Eosinophils
some neonates (7±10). Furthermore, cord-blood Eosinophil granulopoiesis occurs in the fetal liver, and
mononuclear cells from babies delivered to helminth- eosinophilic granulocytes, identi®ed in paraf®n sec-
infected mothers in Kenya, but not to mothers residing tions by staining with haematoxylin-eosin-azure II, are
in North America, can spontaneously produce poly- evident for the ®rst time at 5 weeks in the hepatic
clonal and parasite antigen-speci®c IgE in culture. The laminae (67). Numbers at this site increase gradually
levels induced in the cultured cells corresponded to the over gestation, and then, after 20 weeks of gestation,
level of speci®c IgE measurable in matched cord-blood they appear in the portal areas. The eosinophil
plasma (9). population in the portal areas comprises a greater
number of mature cells than is seen in the hepatic
laminae. This was postulated to re¯ect increasing
Mucosal immunity activity in the portal areas by the component cells that
A functioning mucosal immune system is essential for are also developing and beginning to provide growth
survival in infancy and beyond. IgA and IgM are factors.
important in the ®rst line of defence. In the fetal Although eosinophilia at 3 months of age has been
parotid gland (20±40 weeks), occasional IgM- and associated with a greater risk of the development of
IgA-producing cells were observed, but no cells atopic disease at 18 months of age (68), there are no
producing D, G, or E isotypes were seen (63). The studies of eosinophil numbers and/or function at birth
IgA1 subclass predominates and is mostly J-chain- with regard to the development of allergic disease.
positive. Amylase, lysozyme, and lactoferrin were Like dendritic cells, there are very few studies on either
detectable and most prominent in early fetal life, the phenotype or function of fetal and neonatal
whereas only small amounts of secretory component eosinophils. Interestingly, newborns have less L-
were seen. Postnatally, SC-, IgA-, and IgD-producing selectin on their eosinophils than those of the adult,
cells increase, probably re¯ecting local activation of but fetal eosinophils (23±34 weeks of gestation) have
the immune system by environmental factors (64). adult levels of L-selectin (69, 70). As CD62L is shed
Duodenal expression of secretory component, from the cell surface during activation, the decreased
classes I and II is seen and IgA-, IgM-, and IgG- levels of surface CD62L on newborn eosinophils may
producing cells are detectable from 24±32 weeks of indicate activation of this population, and the process
gestation. Only small amounts of secretory component of labour itself could have had this effect. Moreover,
can be visualized before week 29 of gestation, the eosinophils constituted a large proportion of the

692
 Fetal immune system

granulocytes (42t26%) in these fetal samples; how- during infancy, the overall balance within the
ever, as these samples were collected for diagnostic adaptive immune system remains distorted toward
tests for fetal anomalies, this abundance of eosinophils the Th2 phenotype, resulting in blunted expression of
may re¯ect fetal disorders (71). Th1 immunity at peripheral challenge sites (82), a
failure of the immune deviation mechanisms that
normally regulate induction of Th2 responses at
Postnatal maturation of immune function: release from mucosal surfaces (83), and excessive class switching of
placental control immature B cells toward IgE commitment (84).
The precise cellular target(s) of these stimuli remain
One of the long-standing enigmas of immunology has
to be determined, but it appears likely that antigen-
been the mechanism or mechanisms that facilitate
presenting cells (in particular, dendritic cells) play a
acceptance of the fetal ``allograft'' by the maternal
immune system. In extremis, failure to accept the major role (85). The nature of the molecular signalling
graft, involving the active expression of T-cell between the microbial environment and the immune
immunity against potential HLA antigens expressed system remains to be classi®ed; however, it may be
on fetal tissues, results in placental detachment and predicted that the recently described TOLL receptors
fetal loss, or, when reactivity is less intense, in pre- (86, 87), as well as the high-af®nity receptor for
eclampsia and premature delivery. bacterial lipopolysaccharide (CD14), will be found to
T-cell responses in this context are heavily be central in the process.
Th1-polarized and are dominated by IFN-c, which is
highly toxic to the placenta (46). It is now recognized
that a series of overlapping control mechanisms
operate at the level of the placenta, selectively Transition from fetal to adult-equivalent immune competence:
downregulating Th1 immunity at the fetomaternal time course of changes during infancy and early childhood
interface and within the fetal microenvironment itself. Our current understanding of the postnatal matura-
These include expression of FasL on fetal cells as a tion of immune function in man is restricted mainly
potential means of elimination of activated T cells (72, to comparisons between cells taken from cord blood,
73), and local production of T-cell suppressive as representative of fetal/neonatal life, and those from
tryptophan metabolites via indoleamine 2,3-dioxygen- adults. Knowledge of the kinetics of the changes
ase, which is expressed in syncytiotrophoblasts and occurring postnatally, and associated qualitative/
macrophages (74). In addition, the placenta produces quantitative changes in individual cellular functions,
high levels of a range of mediators which are is exceedingly sparse. However, it is becoming evident
Th2-trophic and/or Th1-suppressive, including IL-4 from aetiologic studies of autoimmunity and particu-
and IL-10 (75), prostaglandin E2 (76), and progester- larly allergy (88, 89) that variations in the speed of
one (77±79). The last-named presumably maximizes this maturation process represent important causative
the likelihood that any environmental antigens/aller- factors in these diseases (see below).
gens that pass across to the developing fetus via the Of particular interest in this context are functions
maternal circulation will elicit Th-cell responses in the associated with expression of Th-cell-dependent immu-
fetal immune system, which is dominated by Th2 (as nity. One broad measure of these functions involves
opposed to Th1) cytokines (4). assessment of the postnatal rate of accumulation of T-
memory cells in the periphery. The available studies
suggest that adult-equivalent levels of T-memory cells,
Microbial stimulation and development of immune as demonstrated by CD45RO expression in the TcRa/b
competence and TcRc/d compartments, are achieved by approxi-
As noted earlier (80), it is clear from the compre- mately the age of 15 years, but the rate at which this
hensive literature relating to domestic and experi- occurs within the population is extremely variable
mental animals that the principal stimuli of postnatal (90±93).
maturation of the immune function in mammals are The generation of some aspects of T-memory is poor
signals from the microbial environment, particularly during infancy (94), despite apparently normal levels of
the commensal micro¯ora of the gastrointestinal tract. initial T-cell activation, but the underlying reasons for
Infections, particularly in the gastrointestinal and this transient de®ciency are not understood. In this
respiratory tracts, may also contribute to this process context, it has been demonstrated in several laboratories
(81). that despite initially high in vitro responses to polyclonal
The principal focus of this late-stage maturation stimuli, T cells from normal infants do not show the
process is upregulation of Th1 functions, which, as sustained proliferation typical of adults (95, 96), and do
noted above, are differentially dampened during fetal not give rise to stable clones at a frequency comparable
life. In the absence of adequate microbial stimulation to adults (95). Holt et al.'s (95) study was cross-sectional

693
Holt and Jones

and hence does not answer the key question of when The potential signi®cance of this transient matura-
incompetent T-cell precursor frequency in children tional de®cit becomes apparent when CD4+ Th-cell
reaches the adult normal range. responses to environmental allergens are examined
The related issue of age-dependent changes in over the same age range. These studies indicate that
cytokine production by Th cells is also not fully resolved. initial fetal responses are of the Th0/Th2 phenotype,
However, it has been reported earlier (97) that IFN-c being dominated by Th2 cytokines (4), and that
production in response to polyclonal stimuli rises ``protection'' against consolidation into potentially
between birth and the age of 5 years, at which time pathogenic Th2-polarized memory is (for inhalant
approximately adult-equivalent levels are achieved. This allergens) achieved via immune deviation during
maturational de®cit in IFN-c production is also infancy toward the Th1 cytokine pattern (101±103).
demonstrable at the T-cell clonal level (95). An ongoing Thus, reduced capacity to generate Th1 responses
prospective cohort study in our laboratories (98) has during infancy, in the form of IFN-c and/or upstream
shown that the postnatal upregulation of IFN-c is Th1-polarizing cytokines, such as IL-12, is likely to
usually delayed until after the age of 1 year, and rises compromise this immune deviation process, thus
steadily thereafter; however, as reported earlier (97), we increasing the risk of developing allergy (88, 89). It
have also noted that variation within the overall is also of interest to note that development of atopy in
population is extremely marked. We have noted too childhood is associated with reduced capacity to
that the postnatal capacity to produce Th2 cytokines develop immunologic memory against BCG immuni-
also rises postnatally, and that this rise occurs earlier (by zation during infancy (104), and slower develop-
4 months of age) and peaks late in infancy, before ment of responses to diphtheria/pertussis/tetanus
declining to adult-equivalent production levels (98). vaccination (105).
This suggests that the Th1-polarization of immune The mechanism or mechanisms underlying this
function characteristic of fetal life may be normally maturational difference in immune function in HR
maintained during early infancy, raising the possibility children remain to be elucidated. The simple explana-
that it may have an as yet uncharacterized protective tion that it represents an exaggeration of the Th2
role (e.g., anti-in¯ammatory) during this early life phase. skew which is characteristic of fetal life does not
In this context, it is also of interest to note that appear to be tenable, given recent ®ndings that the
varying grades of eosinophilia, typi®ed by the presence magnitude of allergen-speci®c Th2 responses in
of these cells in the self-limiting rash erythema toxicum,
neonates who do not develop allergy during infancy
are also very common in this age group (99).
is greater than in those who do (102). However, the
Furthermore, analogous to what has been reported in
difference may be at least partially due to variations
infant mice, human neonates can mount Th1-polarized
in capacity to recognize and/or respond to
responses to potent stimuli such as BCG (100), whereas
Th1-inducing signals from the extrauterine environ-
their responses to milder stimuli (such as acellular
ment, as suggested by the recent ®nding linking
diphtheria/pertussis/tetanus vaccine) are strongly Th2
intensity of atopy with a polymorphism in the CD14
polarized (98).
gene encoding the high-af®nity receptor for bacterial
lipopolysaccharide (106).

Variation in postnatal development of adaptive immune

functions: implications for the pathogenesis of allergic disease
Conclusion
In earlier cross-sectional studies on Th-cell function in
infancy, we identi®ed a relative functional de®ciency It is becoming increasingly clear from recent studies
in children at high genetic risk (HR) of atopy, in that the seeds for expression of a variety of immuno-
comparison to their low-risk (LR) counterparts (95). logically mediated diseases in adulthood are sown
This was demonstrated via limiting dilution analysis of during early postnatal life. During this period, the
overall immunocompetent T-cell precursor frequency, immune system is ®ne-tuning a variety of key functions,
and parallel analysis of cytokine production at the T-cell in the face of direct stimulation from environmental
clonal level. Both Th1 and Th2 cytokine production was signals not previously encountered during fetal life, and
reduced in the HR group relative to LR, but the the response patterns ``learned'' during this period
reduction was greatest for the Th1 cytokine IFN-c (95). persist into adult life.
Our initial interpretation of these ®ndings (95), which The future key to the problem of allergy may lie in
has been borne out by the results of more recent studies comprehensive analysis of this complex maturation/
(88), is that this de®ciency in HR children is indicative of education process, with the long-term aim of redirect-
delayed kinetics in the normal transition from the fetal ing aberrant immune responses at an early stage of
Th2-polarized to the adult Th1-polarized cytokine their development, before diseases such as allergy are
phenotype. fully expressed.

694
 Fetal immune system

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