Microchimerism, an infection-sensitive system influencing immune protection, tolerance, and long-term disease susceptibility across generations

Microchimerism, an infection-sensitive system influencing immune protection, tolerance, and long-term disease susceptibility across generations?

Maternal and fetal microchimerism emerge as dynamic mediators at the interface of infection, immune tolerance, and developmental programming. Vertical transfer of maternal immune cells during gestation—and potentially via breastfeeding—impacts the adaptive arm of the offspring’s
immune system linking maternal microchimerism at birth to enhanced vaccine responsiveness and reduced susceptibility to infectious diseases in early childhood. Interestingly, infectious challenges during pregnancy can reshape bidirectional cell trafficking, impact microchimeric subpopulations and shed light on immune recognition. Importantly, technical advances in isolation, transcriptional profiling, and functional expansion of microchimeric immune cells foster these analyses. And with placental extracellular vesicles showing infection-associated changes in vesicle cargo an interesting subcellular component lines up for biomarker status. This session covers microchimerism as an infection-sensitive system influencing immune protection, tolerance, and long-term disease susceptibility across generations.

Wednesday, 27.05.2026, Day 1

Time: 11:00 – 12:30

The intersection of maternal microchimerism and infectious disease

Whitney Harrington

University of Washington & Seattle Children’s Research Institute, USA

Mothers transmit cells to their offspring in utero and likely via postnatal breastmilk exposure. The transmission of these cells is impacted by maternal immune stimuli in pregnancy including placental malaria, peripheral malaria, HIV, and potentially vaccination. Prior work has demonstrated that these cells are enriched for memory T cell populations, and we hypothesize that they may directly and indirectly impact fetal and postnatal immunity in the offspring. For example, we have found that maternal microchimerism at birth is associated with augmented response to Bacillus Calmette–Guérin (BCG) vaccination and reduced susceptibility to symptomatic malaria, respiratory infection, and non-malaria fever. To better understand the mechanism of this protection, we have recently developed an approach to isolate rare maternal T cells from the offspring and investigate their transcriptional profile. Using this approach and others, we have identified Falciparum malaria-, cytomegalovirus- (CMV), and mycobacterium-specific T cells in select offspring, representing the direct transmission of cellular pathogen-specific immunity. In addition, we have recently developed an approach to massively expand maternal microchimeric T cells to better enable functional screening for potential antigen specificity. Further, we have identified an associated between the presence of maternal cells at birth and altered prenatal immune priming against malaria, suggesting that maternal microchimerism may also indirectly impact fetal immunity. These data suggest that maternal microchimerism plays an important and underappreciated role in providing “active” protection to the offspring against infection.

Gestational ZIKV exposure increases fetal microchimerism, including neural cells

Samantha de Freitas Cavalcante

Samantha de Freitas Cavalcante^1,2; Carolina Mendes Aguiar³; Fabio Barrozo Canto⁴; Selma Maria Bezerra Jerônimo³; Maria Bellio¹; Eduardo Bouth Sequerra⁵

Laboratório de Imunobiologia; Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio de Janeiro
Programa de Pós-Graduação em Microbiologia Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio de Janeiro
Instituto de Medicina Tropical, Universidade Federal do Rio Grande do Norte
Instituto de Biologia, Universidade Federal Fluminense
Instituto do Cérebro, Universidade Federal do Rio Grande do Norte

Fetal microchimeric cells contribute to maternal immune tolerance to fetal antigens. Infectious challenges, however, may disrupt tolerance and elicit immune responses against the fetus. Congenital Zika virus (ZIKV) infection is linked to severe fetal neurological abnormalities, yet the contribution of maternal immune responses to the phenotypic variability observed in the Congenital Zika Syndrome (CZS) remains poorly understood. Here, we investigated whether congenital ZIKV infection alters the.

To assess fetal microchimerism, heterozygous β-actin–GFP males (B6-GFP) were crossed with wild-type C57BL/6 females, enabling detection of embryo-derived cells in maternal circulation. Maternal blood was collected at 5 days post-infection (dpi; injection in the amniotic fluid, 10³ PFU) and analyzed by flow cytometry. ZIKV-infected dams showed increased levels of fetal microchimeric cells compared to controls, with neural stem cells detected exclusively in infected females. Also, the brains of GFP^– embryos show an increase in the number of cells from their siblings.

By using a mouse with young neurons expressing TdTomato, we corroborated the above finding by showing that ZIKV infection leads to the detection TdTomato⁺ cells in the maternal blood. All TdTomato⁺ cells express CD14, suggesting that these neurons undergo phagocytosis.

Finally, analyzing BALB/c females crossed to B6-GFP males and intraperitoneally inoculated with ZIKV (10⁶ PFU), we observed increased fetal cells (H-2b/H-2d double positive cells) in the circulation and in secondary lymphoid organs.

Moreover, analyzing BALB/c females crossed to B6-GFP males and intraperitoneally inoculated with ZIKV (10⁶ PFU), we observed that fetal cells (H-2b/H-2d double positive) seem to accumulate mainly in the spleen of the dam. Together, these findings indicate that congenital ZIKV infection reshapes fetal microchimerism by increasing permeability between the embryonic nervous system and the mother, which potentially impacts on maternal immune tolerance towards fetal antigens during infection.

Placental extracellular vesicles indicate the vertical transfer of maternal microchimeric cells to the fetus in healthy and infection-affected pregnancies

Isabel Graf

Isabel Graf^1,2,, Christopher Urbschat^1,2,, Bente Siebels³, Christian Müller⁴, Anke Diemert⁵, Petra Arck^1,2

¹Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Prenatal Medicine, University Medical Center of Hamburg-Eppendorf, Germany

²Hamburg Center for Translational Immunology

³Section Mass Spectrometry and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf (UKE), Germany

⁴UKE Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Germany

⁵Department of Obstetrics and Prenatal Medicine, University Medical Center Hamburg-Eppendorf, Germany

Background: During pregnancy, maternal (immune) cells are vertically transferred to the fetus. These cells can persist in the offspring, then referred to as maternal microchimeric cells (MMc). There is mounting evidence that MMc can impact the child’s susceptibility to diseases later in life. However, little is known about driving factors and mechanisms of MMc trafficking. This study investigates placental extracellular vesicles (EVs) as messenger of MMc transfer in healthy and infection-affected pregnancies.

Methods: The proteome of serum-derived EVs from healthy and SARS-CoV-2-infected pregnant women was analyzed by imaging flow cytometry and mass spectrometry and correlated with MMc frequencies in cord blood. Murine models were used to validate proteins modulating MMc trafficking.

Results: Maternal SARS-CoV-2-infection led to decreased MMc transfer rates. This was associated with an increased placental EV secretion, along with an altered protein cargo, including downregulation of PSME1, an immunoproteasome component. In a murine model we proof that PSME1 is associated with MMc.

Conclusion: Placental EVs were identified as biomarkers indicating trafficking and regulation of MMc in response to adverse conditions.

Maternal microchimerism at birth associates with reduced odds of non-malarial fever and respiratory tract infections in Tanzanian children

Gitte L. Petersen

Gitte L. Petersen^1,2, Paul T. Edlefsen³, Xiaohong Li⁴, Robert Morrison⁵, Edward Kabyemela⁶, J. Lee Nelson^7,8, Patrick E. Duffy⁵, Michal Fried⁵, Whitney E. Harrington^9,10,11

¹Department of Translational Type 1 Diabetes Research, Steno Diabetes Center Copenhagen, Herlev, Denmark

²Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

³Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA

⁴Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA

⁵Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

⁶School of Diagnostic Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

⁷Translational Science and Therapeutics, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

⁸Department of Medicine, University of Washington, Seattle, Washington, United States of America

⁹Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA

¹⁰Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA

¹¹Department of Global Health, University of Washington, Seattle, Washington, USA

Presenting author: Gitte Lindved Petersen, MSc, PhD

Abstract

The presence of maternal cells in infant cord blood, a phenomenon known as maternal microchimerism, has been previously associated with malaria and respiratory infections in early childhood suggesting a role in immunological responses to infections. Here, we assess the association between cord blood maternal microchimerism and non-malarial infections in Tanzanian children.

We conducted a secondary analysis using a nested birth cohort of 52 children from Muheza, Tanzania, with previously measured cord blood maternal microchimerism and longitudinal records on infections in the first four years of life. The associations between maternal microchimerism and lower and upper respiratory tract infections, diarrhea, and non-malarial fever were estimated using generalized estimating equation models.

In total, 29% of the 52 children in the study screened positive for cord blood maternal microchimerism. Detected versus non-detected maternal microchimerism was associated with 58% lower odds of non-malarial fever (fully adjusted odds ratio (OR): 0.42 [95% CI: 0.18-0.98]) and 28% lower odds of RTI (OR: 0.72 [95% CI: 0.53-0.96]). Lower and upper respiratory tract infections contributed equally to the observed association with any respiratory tract infections (ORs respectively: 0.81 [95% CI: 0.50-1.31] and 0.71 [95% CI: 0.50-1.01]). We did not find any association between maternal microchimerism and odds of diarrhea (OR: 1.63 [95% CI: 0.85-3.13]).

Detectable cord blood maternal microchimerism was associated with lower odds of non-malarial fever and respiratory infections in Tanzanian infants. These findings emphasize that MMc may play an underrecognized role in protection from infection during early childhood.