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Maternal trans-vaccenic acid shapes neonatal T cell development and early-life immune imprinting.

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Title: Maternal trans-vaccenic acid shapes neonatal T cell development and early-life immune imprinting.
Authors: Fan, Hao (AUTHOR), Zheng, Zhong (AUTHOR), Oliphant, Kaitlyn (AUTHOR), Li, Jiacheng (AUTHOR), Mack, Ryan (AUTHOR), Ju, Cheng-Wei (AUTHOR), Trandai, Brandon (AUTHOR), Tu, Jiayi (AUTHOR), Zhang, Freya Q. (AUTHOR), Zhang, Rukang (AUTHOR), Xie, Zhicheng (AUTHOR), Yin, Chunzhao (AUTHOR), Cai, Chufan (AUTHOR), Kennedy, Megan S. (AUTHOR), McNeely, Tess (AUTHOR), Cham, Candace (AUTHOR), Shah, Hardik (AUTHOR), Dong, Lei (AUTHOR), Su, Rui (AUTHOR), Martin, Camilia R. (AUTHOR)
Source: Science. 6/18/2026, Vol. 392 Issue 6804, p1-17. 17p.
Subjects: T cells, Th1 cells, Maternal nutrition, Immunity, Trans fatty acids, Maternally acquired immunity, Breastfeeding
Abstract: How maternal nutrition influences neonatal immune development and imprinting through breastfeeding remains largely unclear. We report that maternal supplementation with trans-vaccenic acid (TVA), the predominant naturally occurring trans-fatty acid in human breast milk, promoted neonatal T cell development in mice. Neonates fed by mothers on a TVA-enriched diet showed an expanded naïve cluster of differentiation 4 (CD4+) T cell population and enhanced adaptive immunity against infection. TVA reprogrammed neonatal naïve CD4+ T cells through a G protein–coupled receptor–CCCTC-binding factor axis and promoted T helper cells (Th1)–skewing by cooperating with the transcription factor TBX21. Early-life exposure to maternal TVA via breastfeeding supported long-lasting antiviral immunity in adulthood. Our findings establish the multifaceted benefits of maternal nutrition and breastfeeding via TVA in promoting infant immune homeostasis and protective immunity. Editor's summary: Milk is a vital nutrient source for young mammals, containing minerals, proteins, carbohydrates and fats. Fan et al. found that the fatty acid trans-vaccenic acid (TVA) could be augmented in the milk of female mice through diet, resulting in increased TVA levels in offspring. TVA-enriched milk promoted CD4 T cell development in pups, stimulating the development of cells with a T helper 1 phenotype. Consuming TVA-enriched milk during the first 3 weeks after birth, but not when given as a supplement after weaning, improved the ability of young mice to respond to viral infection, a benefit that lasted into adulthood. —Sarah H. Ross INTRODUCTION: Early-life nutritional exposures can shape physiology and disease risk across the lifespan, but the mechanisms by which maternal diet influences neonatal immune development remain poorly understood. Human breast milk is widely recognized as a complex biological system in which diverse nutritional and immunomodulatory components act together to support infant development and health. Because its composition is shaped by maternal diet and contains many interacting molecules, mechanistic studies of breast milk's biological effects have been challenging. Consequently, the benefits of breastfeeding are generally attributed to the combined action of multiple components, raising the question of whether a single dietary molecule in breast milk can directly shape neonatal immune development and long-term immune imprinting. RATIONALE: Maternal diet strongly influences the fatty acid composition of breast milk. However, it remains unclear whether a single diet-derived fatty acid delivered through breastfeeding can independently instruct immune development in newborns. Trans-vaccenic acid (TVA) is the predominant naturally occurring trans fatty acid enriched in human breast milk and is derived entirely from the maternal diet as it cannot be synthesized by the human body. Building on our recent work showing that dietary TVA enhances effector CD8⁺ T cell function and anti-tumor immunity in adults, we asked whether maternal TVA could shape neonatal immune development and immunity. RESULTS: We fed nursing female mice a TVA-enriched diet and found that TVA accumulated in breast milk and transferred to pups, raising circulating levels of TVA without affecting body weight. Pups nursed on TVA-enriched milk showed enlarged immune organs and a marked expansion of naïve CD4⁺ T cells, a population that is foundational to adaptive immunity. Multiomics analyses revealed that TVA reprogrammed neonatal naïve CD4⁺ T cells through a defined molecular pathway. TVA inactivated the cell surface receptor GPR43, triggering cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), signaling that increased the activity of the genome-organizing protein CCCTC-binding factor (CTCF). CTCF cooperated with the transcription factor TBX21 and shifted neonatal immune responses from a T helper (Th)2-biased state toward Th1 immunity. Consistent with this mechanism, pups exposed to TVA through breastfeeding—but not those exposed only prenatally—showed improved survival, reduced pathogen burden, and faster T cell responses following infection with influenza A virus or Salmonella. Moreover, neonatal TVA exposure via breastfeeding, but not adult exposure, produced durable immune imprinting, enhancing antiviral immunity in adulthood. TVA treatment of human cord blood–derived naïve CD4⁺ T cells produced similar Th1-promoting effects. In preterm infants, circulating TVA levels correlated with markers of T cell expansion and Th1 immunity, while higher TVA levels in breast milk were associated with reduced bronchopulmonary dysplasia. CONCLUSION: Our findings identify maternal trans-vaccenic acid as a signal linking maternal diet to neonatal immune development. Our study shows that a single dietary molecule can be sufficient to program neonatal T cell development, immunity, and long-term immune imprinting in mice. These results suggest opportunities to optimize maternal diet or infant nutrition to support immune health early in life. Maternal trans-vaccenic acid (TVA) in breast milk programs neonatal T cell development and immune imprinting.: TVA, transferred through breastfeeding, expands neonatal naïve CD4+ T cells and reprograms immunity from a Th2-biased state toward Th1 through a GPR43-cAMP-PKA-CTCF/TBX21 pathway. This remodeling enhances resistance to pathogens in early life and establishes durable immune imprinting that strengthens antiviral immunity in adulthood. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Maternal trans-vaccenic acid shapes neonatal T cell development and early-life immune imprinting.
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  Data: <searchLink fieldCode="AR" term="%22Fan%2C+Hao%22">Fan, Hao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zheng%2C+Zhong%22">Zheng, Zhong</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Oliphant%2C+Kaitlyn%22">Oliphant, Kaitlyn</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Jiacheng%22">Li, Jiacheng</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mack%2C+Ryan%22">Mack, Ryan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ju%2C+Cheng-Wei%22">Ju, Cheng-Wei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Trandai%2C+Brandon%22">Trandai, Brandon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tu%2C+Jiayi%22">Tu, Jiayi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Freya+Q%2E%22">Zhang, Freya Q.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Rukang%22">Zhang, Rukang</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Xie%2C+Zhicheng%22">Xie, Zhicheng</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yin%2C+Chunzhao%22">Yin, Chunzhao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cai%2C+Chufan%22">Cai, Chufan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kennedy%2C+Megan+S%2E%22">Kennedy, Megan S.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22McNeely%2C+Tess%22">McNeely, Tess</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cham%2C+Candace%22">Cham, Candace</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shah%2C+Hardik%22">Shah, Hardik</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Dong%2C+Lei%22">Dong, Lei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Su%2C+Rui%22">Su, Rui</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Martin%2C+Camilia+R%2E%22">Martin, Camilia R.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="DE" term="%22T+cells%22">T cells</searchLink><br /><searchLink fieldCode="DE" term="%22Th1+cells%22">Th1 cells</searchLink><br /><searchLink fieldCode="DE" term="%22Maternal+nutrition%22">Maternal nutrition</searchLink><br /><searchLink fieldCode="DE" term="%22Immunity%22">Immunity</searchLink><br /><searchLink fieldCode="DE" term="%22Trans+fatty+acids%22">Trans fatty acids</searchLink><br /><searchLink fieldCode="DE" term="%22Maternally+acquired+immunity%22">Maternally acquired immunity</searchLink><br /><searchLink fieldCode="DE" term="%22Breastfeeding%22">Breastfeeding</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: How maternal nutrition influences neonatal immune development and imprinting through breastfeeding remains largely unclear. We report that maternal supplementation with trans-vaccenic acid (TVA), the predominant naturally occurring trans-fatty acid in human breast milk, promoted neonatal T cell development in mice. Neonates fed by mothers on a TVA-enriched diet showed an expanded naïve cluster of differentiation 4 (CD4+) T cell population and enhanced adaptive immunity against infection. TVA reprogrammed neonatal naïve CD4+ T cells through a G protein–coupled receptor–CCCTC-binding factor axis and promoted T helper cells (Th1)–skewing by cooperating with the transcription factor TBX21. Early-life exposure to maternal TVA via breastfeeding supported long-lasting antiviral immunity in adulthood. Our findings establish the multifaceted benefits of maternal nutrition and breastfeeding via TVA in promoting infant immune homeostasis and protective immunity. Editor's summary: Milk is a vital nutrient source for young mammals, containing minerals, proteins, carbohydrates and fats. Fan et al. found that the fatty acid trans-vaccenic acid (TVA) could be augmented in the milk of female mice through diet, resulting in increased TVA levels in offspring. TVA-enriched milk promoted CD4 T cell development in pups, stimulating the development of cells with a T helper 1 phenotype. Consuming TVA-enriched milk during the first 3 weeks after birth, but not when given as a supplement after weaning, improved the ability of young mice to respond to viral infection, a benefit that lasted into adulthood. —Sarah H. Ross INTRODUCTION: Early-life nutritional exposures can shape physiology and disease risk across the lifespan, but the mechanisms by which maternal diet influences neonatal immune development remain poorly understood. Human breast milk is widely recognized as a complex biological system in which diverse nutritional and immunomodulatory components act together to support infant development and health. Because its composition is shaped by maternal diet and contains many interacting molecules, mechanistic studies of breast milk's biological effects have been challenging. Consequently, the benefits of breastfeeding are generally attributed to the combined action of multiple components, raising the question of whether a single dietary molecule in breast milk can directly shape neonatal immune development and long-term immune imprinting. RATIONALE: Maternal diet strongly influences the fatty acid composition of breast milk. However, it remains unclear whether a single diet-derived fatty acid delivered through breastfeeding can independently instruct immune development in newborns. Trans-vaccenic acid (TVA) is the predominant naturally occurring trans fatty acid enriched in human breast milk and is derived entirely from the maternal diet as it cannot be synthesized by the human body. Building on our recent work showing that dietary TVA enhances effector CD8⁺ T cell function and anti-tumor immunity in adults, we asked whether maternal TVA could shape neonatal immune development and immunity. RESULTS: We fed nursing female mice a TVA-enriched diet and found that TVA accumulated in breast milk and transferred to pups, raising circulating levels of TVA without affecting body weight. Pups nursed on TVA-enriched milk showed enlarged immune organs and a marked expansion of naïve CD4⁺ T cells, a population that is foundational to adaptive immunity. Multiomics analyses revealed that TVA reprogrammed neonatal naïve CD4⁺ T cells through a defined molecular pathway. TVA inactivated the cell surface receptor GPR43, triggering cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), signaling that increased the activity of the genome-organizing protein CCCTC-binding factor (CTCF). CTCF cooperated with the transcription factor TBX21 and shifted neonatal immune responses from a T helper (Th)2-biased state toward Th1 immunity. Consistent with this mechanism, pups exposed to TVA through breastfeeding—but not those exposed only prenatally—showed improved survival, reduced pathogen burden, and faster T cell responses following infection with influenza A virus or Salmonella. Moreover, neonatal TVA exposure via breastfeeding, but not adult exposure, produced durable immune imprinting, enhancing antiviral immunity in adulthood. TVA treatment of human cord blood–derived naïve CD4⁺ T cells produced similar Th1-promoting effects. In preterm infants, circulating TVA levels correlated with markers of T cell expansion and Th1 immunity, while higher TVA levels in breast milk were associated with reduced bronchopulmonary dysplasia. CONCLUSION: Our findings identify maternal trans-vaccenic acid as a signal linking maternal diet to neonatal immune development. Our study shows that a single dietary molecule can be sufficient to program neonatal T cell development, immunity, and long-term immune imprinting in mice. These results suggest opportunities to optimize maternal diet or infant nutrition to support immune health early in life. Maternal trans-vaccenic acid (TVA) in breast milk programs neonatal T cell development and immune imprinting.: TVA, transferred through breastfeeding, expands neonatal naïve CD4+ T cells and reprograms immunity from a Th2-biased state toward Th1 through a GPR43-cAMP-PKA-CTCF/TBX21 pathway. This remodeling enhances resistance to pathogens in early life and establishes durable immune imprinting that strengthens antiviral immunity in adulthood. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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