Figure 5 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Maternal micro chimerism at birth is positively associated with T cell responses to BCG vaccination. (A) Polyfunctionality score (PFS) at week 7 and week 15 of life by detection of maternal microchimerism (MMc) at birth (N = no [purple], Y = yes [red]). (B) Association between PFS at week 7 (light green) and week 15 (green) of life and level of MMc per 100,000 genomic equivalents (gEq) at birth. Delta represents the adjusted effect size per 10/100,000 gEq. (C) PFS at week 7 and week 15 of life by detection of MMc at the concurrent time point (N = no [purple], Y = yes [red]). (D) Association between PFS at week 7 (light green) and week 15 (green) of life and level of MMc per 100,000 gEq at the concurrent time point. Delta represents the adjusted effect size per 10/100,000 gEq. Horizontal black lines in A and C indicate mean values, and black lines in B and D indicate best fit lines.
Source publication
Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed...
Contexts in source publication
Context 1
... used the COMPASS polyfunctional score (PFS), a clinically validated tool for assessing polyfunctional T cell function (35) to measure CD4 + T cell responses in 33 infants across 48 samples and adjusted for BCG strain (Danish versus Russian), HIV exposure, and infant age in our analyses. Both detection (adjusted coefficient 0.340, P < 0.001; Figure 5A) and level of MMc (adjusted coefficient per 10/100,000 gEq 0.272, P < 0.001; Figure 5B) at birth were positively associated with the PFS. In contrast, concurrent detection or level of MMc in the infant blood at week 7 or 15 was not associated with polyfunctionality of BCG response at those time points ( Figure 5, C and D). ...
Context 2
... used the COMPASS polyfunctional score (PFS), a clinically validated tool for assessing polyfunctional T cell function (35) to measure CD4 + T cell responses in 33 infants across 48 samples and adjusted for BCG strain (Danish versus Russian), HIV exposure, and infant age in our analyses. Both detection (adjusted coefficient 0.340, P < 0.001; Figure 5A) and level of MMc (adjusted coefficient per 10/100,000 gEq 0.272, P < 0.001; Figure 5B) at birth were positively associated with the PFS. In contrast, concurrent detection or level of MMc in the infant blood at week 7 or 15 was not associated with polyfunctionality of BCG response at those time points ( Figure 5, C and D). ...
Context 3
... detection (adjusted coefficient 0.340, P < 0.001; Figure 5A) and level of MMc (adjusted coefficient per 10/100,000 gEq 0.272, P < 0.001; Figure 5B) at birth were positively associated with the PFS. In contrast, concurrent detection or level of MMc in the infant blood at week 7 or 15 was not associated with polyfunctionality of BCG response at those time points ( Figure 5, C and D). Similar associations were found for the functionality score (FS) (Supplemental Figure 1). ...
Citations
... The phenomenon of maternal cells residing in the offspring, and vice versa, is called microchimerism, defined as cells from one individual residing in another genetically distinct individual. 63 Recent findings suggest that this process is often mutually beneficial, possibly promoting genetic fitness by improving subsequent pregnancy outcomes and conferring tumor-suppressing activity in the mother. 64,65 In the case of maternal microchimerism (MM), that is, transfer of cells from mother to fetus, the most commonly transferred immune cells are naive and memory T cells, B cells, NK cells, and monocytes. ...
... 74 Furthermore, the positive role of MM cells extends to vaccine responses. Infants with a higher concentration of MM cells at birth exhibited a more pronounced and efficient CD4 + T cell response toBacillus Calmette-Guerin (BCG) vaccination.63 Another intriguing study reported that maternal cells were able to stimulate immunesuppressive Tregs in female offspring, specifically Tregs tailored to target non-inherited maternal antigens (NIMA).65 ...
Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long‐term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal‐offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota‐derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue‐specific immune education to offspring. We propose a “maternal‐driven immune education” hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.
... We recently reported that iHEU had significantly lower levels of maternal microchimerism (MMc) at birth compared to iHU, and that lower MMc at birth was associated with attenuated response to BCG vaccination (7). ...
... MMc quantitation in cellular subsets. Human leukocyte antigen (HLA) and non-HLA typing had been previously conducted for all mothers and infants to identify a maternal-specific allele for each pair, as described elsewhere (7). The maternal-specific allele identified for each maternal-infant pair was selectively amplified from gDNA in each sorted cell population using a panel of previously developed quantitate PCR (qPCR) assays (11). ...
Infants exposed to HIV but uninfected (iHEU) display altered cellular immunity and are at increased risk of infection through poorly understood mechanisms. We previously reported that iHEU have lower levels of maternal microchimerism (MMc), maternal cells transferred to the offspring in utero/during breastfeeding. We evaluated MMc levels in T cell subsets in iHEU and HIV unexposed infants (iHU) to determine whether a selective deficiency in MMc may contribute to altered cellular immunity. Across all infants, MMc levels were highest in CD8+ T cells; however, the level of MMc in the CD8 T cell subset was significantly lower in iHEU compared to iHU.
... In addition to antibodies, maternal cells are transferred to the fetus during pregnancy and have an impact on the developing fetal immune system [109]. For example, maternal micro-chimerism, the bidirectional transfer of genetically distinct cells between the mother and fetus, was associated with an improved infant polyfunctional CD4 response to BCG vaccination in South African infants [110]. Maternal vaccine antigens have been shown to prime the infant's B and T cell immune responses [84,111,112]. ...
Prenatal maternal immunization is an effective tool to protect mothers and infants from poor health outcomes due to infectious diseases. We provide an overview of the rationale for the use of prenatal vaccines, discuss the immunologic environment of the maternal–fetal interface including the impact of maternal vaccines prenatally and subsequently on the infant’s immune response, and review vaccines currently recommended in pregnancy and landscape for the future of maternal vaccination. This review aims to provide an understanding of the recent history and progress made in the field and highlight the importance of continued research and development into new vaccines for pregnant populations.
... Во время физиологически текущей беременности в одном миллилитре материнской крови выявляется всего одна-две клетки плода, включая моноциты, В-и Т-лимфоциты, эритроциты с ядрами и гемопоэтические предшественники [24]. Представлены убедительные доказательства перемещения клеток грудного молока от матери к тканям и слизистой оболочке младенца [7,37], лежащего в основе материнского микрохимеризма, вызванного грудным вскармливанием [20,79], который может играть ключевую роль в развитии иммунитета у младенцев [20,24,34,79]. ...
... Во время физиологически текущей беременности в одном миллилитре материнской крови выявляется всего одна-две клетки плода, включая моноциты, В-и Т-лимфоциты, эритроциты с ядрами и гемопоэтические предшественники [24]. Представлены убедительные доказательства перемещения клеток грудного молока от матери к тканям и слизистой оболочке младенца [7,37], лежащего в основе материнского микрохимеризма, вызванного грудным вскармливанием [20,79], который может играть ключевую роль в развитии иммунитета у младенцев [20,24,34,79]. ...
... Грудное молоко играет роль материнской крови, поставляя материнские растворимые факторы (макромолекулы, иммуноглобулины, цитокины) и иммунологически активные клетки молока [79]. Материнские клетки и антигены влияют на иммунную систему плода посредством индукции толерантности и стимуляции адаптивного иммунного ответа [7,20]. ...
Recent expansion of fundamental knowledge on the physiology of lactation, and breast milk exosomes, stem cell biology, mother-child interactions from prenatal period to postnatal development requires a progressive, dynamic view from the scientific community and practicing physicians when analyzing known, generally accepted clinical phenomena and patterns (development of the immune system of infants and young children, natural and artificial feeding, features of postnatal development and growth of organs and tissues in children born prematurely). The components of the mother-breast-milk-infant triad are closely related to each other and influence developmental trajectory of the infant. According to modern concepts, breast milk of a nursing woman is a “living, metabolic / endocrine signaling system”, which may be considered an “immune organ” significant for postnatal growth and body programming of a premature baby. A valuable phenomenon of early postnatal development is actively discussed in the special literature, i,e., “microchimerism” caused by breastfeeding which, according to modern concepts, may play a key role in development of immune system and the whole body. Absence of protective (immunomodulatory and regenerative) effects of breast milk from a nursing woman on the spontaneous, uncorrectable impact of adverse factors of prematurity is likely predispose for remodeling and dysfunction of heart in prematurely born children, and, at longer range, in adults. The young children born prematurely show a unique cardiac phenotype characterized by reduced biventricular volume, relatively lower systolic and diastolic function, disproportionate muscle mass gain, clinically manifesting by increased risk of cardiovascular disease, hypertension, and decreased exercise tolerance. Hence, the premature birth may be considered a chronic disease state. Therefore, the natural feeding which provides a natural evolutionarily protective mechanism for the child’s heart should be attributed to the fundamental factors that play a vital role in prevention of cardiovascular diseases in prematurely born children and at later life periods.
... More recent findings suggest that postnatal depletion of maternal cells modified the maturation of natural killer cells and T-lymphocytes [16]. In humans, infants with detectable maternal microchimerism at birth were shown to have an improved polyfunctional CD4+ T-cell response to the BCG vaccine [17]. Recently, Harrington's group described exclusive breastfeeding as a determinant of higher levels of microchimeric cell density (adjusted RR 4.05; 95% CI, 0.85-19.44, ...
... Recently, Harrington's group described exclusive breastfeeding as a determinant of higher levels of microchimeric cell density (adjusted RR 4.05; 95% CI, 0.85-19.44, p = 0.080) [17], but has not yet been able to discriminate cell trafficking from tolerogenic activity. Precise measurements of microchimeric cell density per organ and its evolution over time are lacking in both animal and human models. ...
... Female cells were identified in almost two-thirds of patients. The reported prevalence of microchimerism is consistent with previous reports ranging from 20% to 60% [17,[24][25][26][27][28][29][30]. The reasons for the inability to detect female cells in some children may rely on the sensitivity of the technique. ...
The factors influencing mother-to-child cell trafficking and persistence over children’s lives have yet to be established. The quantification of maternal microchimerism was previously reported through HLA-based approaches, which introduced bias regarding the tolerogenic environment. We aimed to identify cells of maternal origin irrespective of the HLA repertoire and to ascertain the determinants of microchimeric cells. This case–control study enrolled 40 male infants attending pediatric surgery from January 2022 to October 2022. Female cells were quantified in infants’ tonsil tissue by using cytogenetic fluorescent in situ hybridization (FISH) coupled with optimized automated microscopy. Out of the 40 infants, half (47.4%) had been breastfed for more than one month, a quarter for less a month, and 10 children (26.3%) were never breastfed. XX cells were observed in male tonsils in two-thirds of participants at a median density of 5 cells per 100,000 cells. In univariate analyses, child age was negatively associated with a high female cell density. In exploratory multivariate analyses, previous breastfeeding is a likely determinant of the persistence of these cells in the host, as well as the rank among siblings. Part of the benefit of breastmilk for child health may therefore be driven by breastfeeding-related microchimerism.
... Recently, the differences in maternal microchimerism between CHEU and CHUU were investigated as a potential mediator of altered T-cell responses [71]. Microchimerism is the transfer of maternal cells to the fetus during pregnancy. ...
... This implies that early ART initiation, leading to increased CD4+ T-cell counts, as well as the recovery of immune dysregulation or placental inflammation, may 'normalize' the extent of maternal microchimerism in CHEU. The authors suggested that lower maternal cells in CHEU at birth may, at least in part, be responsible for the attenuated response of CHEU towards the BCG vaccine [71]. ...
With the global rollout of mother-to-child prevention programs for women living with HIV, vertical transmission has been all but eliminated in many countries. However, the number of children who are exposed in utero to HIV and antiretroviral therapy (ART) is ever-increasing. These children who are HIV-exposed-but-uninfected (CHEU) are now well recognized as having persistent health disparities compared to children who are HIV-unexposed–and-uninfected (CHUU). Differences reported between these two groups include immune dysfunction and higher levels of inflammation, cognitive and metabolic abnormalities, as well as increased morbidity and mortality in CHEU. The reasons for these disparities remain largely unknown. The present review focuses on a proposed link between immunometabolic aberrations and clinical pathologies observed in the rapidly expanding CHEU population. By drawing attention, firstly, to the significance of the immune and metabolic alterations observed in these children, and secondly, the impact of their healthcare requirements, particularly in low- and middle-income countries, this review aims to sensitize healthcare workers and policymakers about the long-term risks of in utero exposure to HIV and ART.
... In mice, breastmilk-derived maternal helminth-specific T cells were protective in the offspring upon challenge with the same helminth 18 , and in lambs, breastmilkderived tetanus-specific T cells enhanced the response to tetanus vaccination in the offspring 21 . Human breastmilk maternal microchimerism has not been conclusively demonstrated, although we recently found in a cohort of infants that maternal microchimerism increased up to 3 months of age and was positively associated with breastfeeding 22 . These data emphasize the potential for breastmilk-acquired maternal T cells to become resident in the infant and provide an underrecognized form of passive protection. ...
Human breastmilk is rich in T cells; however, their specificity and function are largely unknown. We compared the phenotype, diversity, and antigen specificity of T cells in the breastmilk and peripheral blood of lactating individuals who received SARS-CoV-2 mRNA vaccination. Relative to blood, breastmilk contained higher frequencies of T effector and central memory populations that expressed mucosal-homing markers. T cell receptor (TCR) sequence overlap was limited between blood and breastmilk. Overabundant breastmilk clones were observed in all individuals, were diverse, and contained CDR3 sequences with known epitope specificity including to SARS-CoV-2 Spike. SARS-CoV-2 Spike-specific TCRs were more frequent in breastmilk compared to blood and expanded in breastmilk following a third mRNA vaccine dose. Our observations indicate that the lactating breast contains a distinct T cell population that can be modulated by maternal vaccination with potential implications for infant passive protection.
... Contrasting consequences of MMc on the progeny immune system have been proposed. As a beneficial effect, MMc was speculated to be able to stimulate the maturation of the nascent immune system (Kinder et al., 2017), with promising results suggesting MMc promotes monocytes and T cells' differentiation and responses (Balle et al., 2022;Stelzer et al., 2021). However, while mutual tolerance is the norm, scarce MMc-induced immune perturbations may lead to auto-or alloreactive immune conflicts (Leveque et al., 2014;Müller et al., 2001)an etiopathogenesis formulated as the materno-fetal immune disease hypothesis Muraji et al., 2009). ...
... Maternal cells transferred during pregnancy engraft in the fetus where they are reported to promote fetal tolerance toward themselves and fetal immune development (Stelzer et al., 2021). However, whether their persistence after birth is coincidental or can be explained by further functions of MMc in postnatal life is still under debate; with the enhancement of immune responses (Balle et al., 2022) and cross-generational reproductive fitness (Kinder et al., 2015) postulated as some of these functions. In this study, we hypothesize a new postnatal role of maternal cells in suppressing the activation of neonatal NK and T lymphocytes. ...
... At first glance, these results appear to be in disagreement with previous studies suggesting MMc enhances immune development, in particular T cell immunity (Balle et al., 2022;Kinder et al., 2017;Stelzer et al., 2021). Notably, MMc was reported to promote fetal CD8+ T cell expansion and immunity against viral infections (Stelzer et al., 2021), such that we expected to observe fewer and more immature T cells in our MMc-depleted samples. ...
The maternal cells transferred into the fetus during gestation persist long after birth in the progeny. These maternal cells have been hypothesized to promote the maturation of the fetal immune system in utero but there are still significant gaps in our knowledge of their potential roles after birth. To provide insights into these maternal cells’ postnatal functional roles, we set up a transgenic mouse model to specifically eliminate maternal cells in the neonates by diphtheria toxin injection and confirmed significant depletion in the spleens. We then performed immunophenotyping of the spleens of two-week-old pups by mass cytometry to pinpoint the immune profile differences driven by the depletion of maternal cells in early postnatal life. We observed a heightened expression of markers related to activation and maturation in some natural killer and T cell populations. We hypothesize these results to indicate a potential postnatal regulation of lymphocytic responses by maternal cells. Together, our findings highlight an immunological influence of maternal microchimeric cells postnatally, possibly protecting against adverse hypersensitivity reactions of the neonate at a crucial time of new encounters with self and environmental antigens.
Background
Maternal priming with bacille Calmette-Guérin (BCG) has been associated with reduced mortality in male offspring. We investigated this association in a cohort of healthy BCG-vaccinated neonates.
Methods
This observational study within a randomized controlled trial comparing different BCG strains was conducted in Guinea-Bissau from 2017 to 2020. As part of trial inclusion procedures, on the day of discharge from the maternity ward, maternal BCG scar status was evaluated by visual inspection, followed by offspring BCG and polio vaccination. Through mortality data collected at telephone interviews at 6 weeks and 6 months of age, we assessed all-cause mortality risk in Cox proportional hazards models adjusted for maternal schooling and BCG strain, providing adjusted mortality rate ratios (aMRRs).
Results
In total, 64% (11 070/17 275) of mothers had a BCG scar, which was not associated with admission risk, admission severity, or all-cause mortality for females and the overall sample. By 6 months of age, the mortality rate (MR) was 4.1 (200 deaths/4919 person-years) for the maternal BCG scar cohort and 5.2 (139/2661) for no maternal scar (aMRR, 0.86; 95% Confidence Interval [CI], .69–1.06). In males, 6-month MRs were 4.3 (109 deaths/2531 person-years) for maternal BCG scar vs 6.3 (87/1376) for no scar (aMRR, 0.74; 95% CI, .56–.99). In females, 6-month MRs were 3.8 (91 deaths/2388 person-years) vs 4.0 (52/1286), respectively (aMRR, 1.04; 95% CI, .74–1.47; for interaction with sex, P = .16).
Conclusions
While we cannot rule out an association in females, being born to a mother with a BCG scar reduced the risk of death during early infancy for BCG-vaccinated males, reproducing findings from previous studies.
