Maternal-fetal microchimerism is a fascinating phenomenon in which maternal cells migrate to the tissues of the offspring during both pregnancy and breastfeeding. These cells primarily consist of leukocytes and stem cells. Remarkably, these maternal cells possess functional potential in the offspring and play a significant role in shaping their immune system development. T lymphocytes, a cell population mainly found in various tissues of the offspring, have been identified as the major cell type derived from maternal microchimerism. These T lymphocytes not only exert effector functions but also influence the development of the offspring's T lymphocytes in the thymus and the maturation of B lymphocytes in the lymph nodes. Furthermore, the migration of maternal leukocytes also facilitates the transfer of immune memory across generations. Maternal microchimerism has also been observed to address immunodeficiencies in the offspring. This review article focuses on investigating the impact of maternal cells transported within maternal microchimerism on the immune system development of the offspring, as well as elucidating the effector functions of maternal cells that migrate through the placenta and breast milk to reach the offspring.

Laboratory of Cell Immunology Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

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Nelson JL. The otherness of self: microchimerism in health and disease. Trends Immunol. 2012;33:421–427. doi: 10.1016/j.it.2012.03.002. PubMed DOI PMC

Loubière LS, Lambert NC, Flinn LJ, Erickson TD, Yan Z, Guthrie KA, Vickers KT, Nelson JL. Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Lab Invest. 2006;86:1185–1192. doi: 10.1038/labinvest.3700471. PubMed DOI

Vernochet C, Caucheteux SM, Kanellopoulos-Langevin C. Bi-directional Cell Trafficking Between Mother and Fetus in Mouse Placenta. Placenta. 2007;28:639–649. doi: 10.1016/j.placenta.2006.10.006. PubMed DOI

Stelzer IA, Urbschat C, Schepanski S, Thiele K, Triviai I, Wieczorek A, Alawi M, et al. Vertically transferred maternal immune cells promote neonatal immunity against early life infections. Nat Commun. 2021;12:4706. doi: 10.1038/s41467-021-24719-z. PubMed DOI PMC

Wang Y, Iwatani H, Ito T, Horimoto N, Yamato M, Matsui I, Imai E, Hori M. Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. Biochem Biophys Res Commun. 2004;325:961–967. doi: 10.1016/j.bbrc.2004.10.105. PubMed DOI

Boddy AM, Fortunato A, Wilson Sayres M, Aktipis A. Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb. BioEssays. 2015;37:1106–1118. doi: 10.1002/bies.201500059. PubMed DOI PMC

Rao AS, Thomson AW, Shapiro R, Starzl TE. Chimerism after whole organ transplantation: its relationship to graft rejection and tolerance induction. Curr Opin Nephrol Hypertens. 1994;3:589–595. doi: 10.1097/00041552-199411000-00005. PubMed DOI

Stelzer IA, Thiele K, Solano ME. Maternal microchimerism: lessons learned from murine models. J Reprod Immunol. 2015;108:12–25. doi: 10.1016/j.jri.2014.12.007. PubMed DOI

Dutta P, Molitor-Dart M, Bobadilla JL, Roenneburg DA, Yan Z, Torrealba JR, Burlingham WJ. Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice. Blood. 2009;114:3578–3587. doi: 10.1182/blood-2009-03-213561. PubMed DOI PMC

Cabinian A, Sinsimer D, Tang M, Zumba O, Mehta H, Toma A, Sant'Angelo D, et al. Transfer of Maternal Immune Cells by Breastfeeding: Maternal Cytotoxic T Lymphocytes Present in Breast Milk Localize in the Peyer's Patches of the Nursed Infant. PLoS One. 2016;11:e0156762. doi: 10.1371/journal.pone.0156762. PubMed DOI PMC

Stevens AM, Hermes HM, Kiefer MM, Rutledge JC, Lee Nelson J. Chimeric Maternal Cells with Tissue-Specific Antigen Expression and Morphology Are Common in Infant Tissues. Pediatr Dev Pathol. 2009;12:337–346. doi: 10.2350/08-07-0499.1. PubMed DOI PMC

Hassiotou F, Heath B, Ocal O, Filgueira L, Geddes D, Hartmann P, Wilkie T. Breastmilk stem cell transfer from mother to neonatal organs. FASEB J. 2014;28(Suppl 1):216.4. doi: 10.1096/fasebj.28.1_supplement.216.4. DOI

Dutta P, Burlingham WJ. Stem cell microchimerism and tolerance to non-inherited maternal antigens. Chimerism. 2010;1:2–10. doi: 10.4161/chim.1.1.12667. PubMed DOI PMC

Cuddapah Sunku C, Gadi V, de Laval de Lacoste B, Guthrie KA, Nelson JL. Maternal and fetal microchimerism in granulocytes. Chimerism. 2010;1:11–14. doi: 10.4161/chim.1.1.13098. PubMed DOI PMC

Mauer AM, Athens JW, Ashenbrucker H, Cartwright GE, Wintrobe MM. Leukokinetic Studies. Ii. A Method For Labeling Granulocytes In Vitro With Radioactive Diisopropylfluorophosphate (DFP32) J Clin Invest. 1960;39:1481–1486. doi: 10.1172/JCI104167. PubMed DOI PMC

Wrenshall LE, Stevens ET, Smith DR, Miller JD. Maternal microchimerism leads to the presence of interleukin-2 in interleukin-2 knock out mice: Implications for the role of interleukin-2 in thymic function. Cell Immunol. 2007;245:80–90. doi: 10.1016/j.cellimm.2007.04.002. PubMed DOI PMC

Arvola M, Gustafsson E, Svensson L, Jansson L, Holmdahl R, Heyman B, Okabe M, Mattsson R. Immunoglobulin-Secreting Cells of Maternal Origin Can Be Detected in B Cell-Deficient Mice. Biol Reprod. 2000;63:1817–1824. doi: 10.1095/biolreprod63.6.1817. PubMed DOI

Fujimoto K, Nakajima A, Hori S, Irie N. Whole embryonic detection of maternal microchimeric cells highlights significant differences in their numbers among individuals. PLoS One. 2021;16:e0261357. doi: 10.1371/journal.pone.0261357. PubMed DOI PMC

Berry SM, Hassan SS, Russell E, Kukuruga D, Land S, Kaplan J. Association of Maternal Histocompatibility at Class II HLA Loci with Maternal Microchimerism in the Fetus. Pediatr Res. 2004;56:73–78. doi: 10.1203/01.PDR.0000129656.10005.A6. PubMed DOI

Kaplan J, Land S. Influence of Maternal-Fetal Histocompatibility and MHC Zygosity on Maternal Microchimerism. J Immunol. 2005;174:7123–7128. doi: 10.4049/jimmunol.174.11.7123. PubMed DOI

Kinder JM, Jiang TT, Ertelt JM, Xin L, Strong BS, Shaaban AF, Way SS. Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells. Cell. 2015;162:505–515. doi: 10.1016/j.cell.2015.07.006. PubMed DOI PMC

Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee T-H, et al. Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero. Science. 2008;322:1562–1565. doi: 10.1126/science.1164511. PubMed DOI PMC

Hossain S, Mihrshahi S. Exclusive Breastfeeding and Childhood Morbidity: A Narrative Review. Int J Environ Res Public Health. 2022;19:14804. doi: 10.3390/ijerph192214804. PubMed DOI PMC

Karlmark KR, Haddad ME, Donato X-C, Martin GV, Bretelle F, Lesavre N, Cocallemen J-F, et al. Grandmaternal cells in cord blood. eBioMedicine. 2021;74:103721. doi: 10.1016/j.ebiom.2021.103721. PubMed DOI PMC

Shimamura M, Ohta S, Suzuki R, Yamazaki K. Transmission of maternal blood cells to the fetus during pregnancy: detection in mouse neonatal spleen by immunofluorescence flow cytometry and polymerase chain reaction. Blood. 1994;83:926–930. doi: 10.1182/blood.V83.4.926.926. PubMed DOI

Hall J, Lingenfelter P, Adams S, Lasser D, Hansen J, Bean M. Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization. Blood. 1995;86:2829–2832. doi: 10.1182/blood.V86.7.2829.2829. PubMed DOI

Piotrowski P, Croy BA. Maternal Cells are Widely Distributed in Murine Fetuses in Utero1. Biol Reprod. 1996;54:1103–1110. doi: 10.1095/biolreprod54.5.1103. PubMed DOI

Su EC, Johnson KL, Tighiouart H, Bianchi DW. Murine Maternal Cell Microchimerism: Analysis Using Real-Time PCR and In Vivo Imaging. Biol Reprod. 2008;78:883–887. doi: 10.1095/biolreprod.107.063305. PubMed DOI PMC

Darby MG, Chetty A, Mrjden D, Rolot M, Smith K, Mackowiak C, Sedda D, et al. Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring. Sci Adv. 2019;5:eaav3058. doi: 10.1126/sciadv.aav3058. PubMed DOI PMC

Ståhlberg A, El-Heliebi A, Sedlmayr P, Kroneis T. Unravelling the biological secrets of microchimerism by single-cell analysis. Brief Funct Genomics. 2018;17:255–264. doi: 10.1093/bfgp/elx027. PubMed DOI PMC

Fujimoto K, Nakajima A, Hori S, Tanaka Y, Shirasaki Y, Uemura S, Irie N. Whole-embryonic identification of maternal microchimeric cell types in mouse using single-cell RNA sequencing. Sci Rep. 2022;12:18313. doi: 10.1038/s41598-022-20781-9. PubMed DOI PMC

Camacho-Morales A, Caba M, García-Juárez M, Caba-Flores MD, Viveros-Contreras R, Martínez-Valenzuela C. Breastfeeding Contributes to Physiological Immune Programming in the Newborn. Front Pediatr. 2021;9:744104. doi: 10.3389/fped.2021.744104. PubMed DOI PMC

Ross SH, Cantrell DA. Signaling and Function of Interleukin-2 in T Lymphocytes. Annu Rev Immunol. 2018;36:411–433. doi: 10.1146/annurev-immunol-042617-053352. PubMed DOI PMC

Schorle H, Holtschke T, Hünig T, Schimpl A, Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991;352:621–624. doi: 10.1038/352621a0. PubMed DOI

Letterio JJ, Geiser AG, Kulkarni AB, Roche NS, Sporn MB, Roberts AB. Maternal Rescue of Transforming Growth Factor-β 1 Null Mice. Science. 1994;264:1936–1938. doi: 10.1126/science.8009224. PubMed DOI

Kanaan SB, Gammill HS, Harrington WE, De Rosa SC, Stevenson PA, Forsyth AM, Allen J, et al. Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant. Oncoimmunology. 2017;6:e1311436. doi: 10.1080/2162402X.2017.1311436. PubMed DOI PMC

Kanold AMJ, Westgren M, Götherström C. Cellular Subsets of Maternal Microchimerism in Umbilical Cord Blood. Cell Transplant. 2019;28:522–528. doi: 10.1177/0963689718779783. PubMed DOI PMC

Bertrand JY, Jalil A, Klaine M, Jung S, Cumano A, Godin I. Three pathways to mature macrophages in the early mouse yolk sac. Blood. 2005;106:3004–3011. doi: 10.1182/blood-2005-02-0461. PubMed DOI

Balounová J, Šplíchalová I, Dobešová M, Kolář M, Fišer K, Procházka J, Sedlacek R, et al. Toll-like receptor 2 expression on c-kit+ cells tracks the emergence of embryonic definitive hematopoietic progenitors. Nat Commun. 2019;10:5176. doi: 10.1038/s41467-019-13150-0. PubMed DOI PMC

Witkowska-Zimny M, Kaminska-El-Hassan E. Cells of human breast milk. Cell Mol Biol Lett. 2017;22:11. doi: 10.1186/s11658-017-0042-4. PubMed DOI PMC

Laouar A. Maternal Leukocytes and Infant Immune Programming during Breastfeeding. Trends Immunol. 2020;41:225–239. doi: 10.1016/j.it.2020.01.005. PubMed DOI

Boes M, Cerny J, Massol R, den Brouw MO, Kirchhausen T, Chen J, Ploegh HL. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature. 2002;418:983–988. doi: 10.1038/nature01004. PubMed DOI

Pačes J, Knížková K, Tušková L, Grobárová V, Zadražil Z, Boes M, Černý J. MHC II - EGFP knock-in mouse model is a suitable tool for systems and quantitative immunology. Immunol Lett. 2022;251–252:75–85. doi: 10.1016/j.imlet.2022.10.007. PubMed DOI

Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45:593–605. doi: 10.1002/dvg.20335. PubMed DOI

Crago SS, Prince SJ, Pretlow TG, McGhee JR, Mestecky J. Human colostral cells. I. Separation and characterization. Clin Exp Immunol. 1979;38:585–597. PubMed PMC

Babu ST, Niu X, Raetz M, Savani RC, Hooper LV, Mirpuri J. Maternal high-fat diet results in microbiota-dependent expansion of ILC3s in mice offspring. JCI Insight. 2018;3:e99223. doi: 10.1172/jci.insight.99223. PubMed DOI PMC

Hassiotou F, Hepworth AR, Metzger P, Lai CT, Trengove N, Hartmann PE, Filgueira L. Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. Clin Transl Immunol. 2013;2:e3. doi: 10.1038/cti.2013.1. PubMed DOI PMC

Molès JP, Tuaillon E, Kankasa C, Bedin A-S, Nagot N, Marchant A, McDermid JM, Van de Perre P. Breastmilk cell trafficking induces microchimerism-mediated immune system maturation in the infant. Pediatr Allergy Immunol. 2018;29:133–143. doi: 10.1111/pai.12841. PubMed DOI

Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014;10:1171–1184. doi: 10.1586/1744666X.2014.942288. PubMed DOI PMC

Hassiotou F, Geddes DT, Hartmann PE. Cells in Human Milk: State of the Science. J Hum Lact. 2013;29:171–182. doi: 10.1177/0890334413477242. PubMed DOI

Valverde-Villegas JM, Durand M, Bedin A-S, Rutagwera D, Kankasa C, Tuaillon E, Nagot N, et al. Large Stem/Progenitor-Like Cell Subsets can Also be Identified in the CD45 - and CD45 +/High Populations in Early Human Milk. J Hum Lact. 2020;36:303–309. doi: 10.1177/0890334419885315. PubMed DOI

Sabbaj S, Ghosh MK, Edwards BH, Leeth R, Don Decker W, Goepfert PA, Aldrovandi GM. Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans. J Immunol. 2005;174:2951–2956. doi: 10.4049/jimmunol.174.5.2951. PubMed DOI

Tuaillon E, Valéa D, Becquart P, Al Tabaa Y, Meda N, Bollore K, Van de Perre P, Vendrell J-P. Human milk-derived B cells: a highly activated switched memory cell population primed to secrete antibodies. J Immunol. 2009;182:7155–7162. doi: 10.4049/jimmunol.0803107. PubMed DOI

Pačes J, Grobárová V, Zadražil Z, Knížková K, Malinská N, Tušková L, Boes M, Černý J. MHC II-EGFP Knock-in Mouse Model. Curr Protoc. 2023;3:e925. doi: 10.1002/cpz1.925. PubMed DOI

Ikebuchi R, Fujimoto M, Moriya T, Kusumoto Y, Kobayashi K, Tomura M. T cells are the main population in mouse breast milk and express similar profiles of tight junction proteins as those in mammary alveolar epithelial cells. J Reprod Immunol. 2020;140:103137. doi: 10.1016/j.jri.2020.103137. PubMed DOI

Wirt DP, Adkins LT, Palkowetz KH, Schmalstieg FC, Goldman AS. Activated and memory T lymphocytes in human milk. Cytometry. 1992;13:282–290. doi: 10.1002/cyto.990130310. PubMed DOI

Pillay J, Den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, Borghans JAM, Tesselaar K, Koenderman L. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116:625–627. doi: 10.1182/blood-2010-01-259028. PubMed DOI

Yu JC, Khodadadi H, Malik A, Davidson B, da Silva Lopes Salles É, Bhatia J, Hale VL, Baban B. Innate Immunity of Neonates and Infants. Front Immunol. 2018;9:1759. doi: 10.3389/fimmu.2018.01759. PubMed DOI PMC

Weinberger B, Laskin DL, Mariano TM, Sunil VR, DeCoste CJ, Heck DE, Gardner CR, Laskin JD. Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants. J Leukoc Biol. 2001;70:969–976. doi: 10.1189/jlb.70.6.969. PubMed DOI PMC

Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009;113:6419–6427. doi: 10.1182/blood-2008-07-171629. PubMed DOI PMC

Hughes A, Brock JH, Parrott DM, Cockburn F. The interaction of infant formula with macrophages: effect on phagocytic activity, relationship to expression of class II MHC antigen and survival of orally administered macrophages in the neonatal gut. Immunology. 1988;64:213–218. PubMed PMC

Ichikawa M, Sugita M, Takahashi M, Satomi M, Takeshita T, Araki T, Takahashi H. Breast milk macrophages spontaneously produce granulocyte-macrophage colony-stimulating factor and differentiate into dendritic cells in the presence of exogenous interleukin-4 alone. Immunology. 2003;108:189–195. doi: 10.1046/j.1365-2567.2003.01572.x. PubMed DOI PMC

Geissmann F, Jung S, Littman DR. Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties. Immunity. 2003;19:71–82. doi: 10.1016/S1074-7613(03)00174-2. PubMed DOI

Zheng Y, Corrêa-Silva S, de Souza EC, Rodrigues RM, da Fonseca FAM, Gilio AE, Carneiro-Sampaio M, Palmeira P. Macrophage profile and homing into breast milk in response to ongoing respiratory infections in the nursing infant. Cytokine. 2020;129:155045. doi: 10.1016/j.cyto.2020.155045. PubMed DOI

Medzhitov R, Schneider DS, Soares MP. Disease Tolerance as a Defense Strategy. Science. 2012;335:936–941. doi: 10.1126/science.1214935. PubMed DOI PMC

Leyva-Cobián F, Clemente J. Phenotypic characterization and functional activity of human milk macrophages. Immunol Lett. 1984;8:249–256. doi: 10.1016/0165-2478(84)90004-X. PubMed DOI

Geijtenbeek TBH, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, et al. DC-SIGN, a Dendritic Cell-Specific HIV-1-Binding Protein that Enhances trans-Infection of T Cells. Cell. 2000;100:587–597. doi: 10.1016/S0092-8674(00)80694-7. PubMed DOI

Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109–1118. doi: 10.1084/jem.179.4.1109. PubMed DOI PMC

Bedin A, Molès J, Rutagwera D, Nagot N, Kankasa C, Tylleskär T, Valverde-Villegas JM, et al. MAIT cells, TCR γδ+ cells and ILCs cells in human breast milk and blood from HIV infected and uninfected women. Pediatr Allergy Immunol. 2019;30:479–487. doi: 10.1111/pai.13037. PubMed DOI

Cérbulo-Vázquez A, Hernández-Peláez G, Arriaga-Pizano LA, Bautista-Pérez P, Romero-Venado J, Flores-González JC, Figueroa-Damian R, et al. Characterization of CD127 − CD25 ++ Treg from human colostrum. Am J Reprod Immunol. 2018;79:e12806. doi: 10.1111/aji.12806. PubMed DOI

Rudloff HE, Schmalstieg FC, Mushtaha AA, Palkowetz KH, Liu SK, Goldman AS. Tumor Necrosis Factor-α in Human Milk. Pediatr Res. 1992;31:29–33. doi: 10.1203/00006450-199201000-00005. PubMed DOI

Hawkes JS, Bryan DL, James MJ, Gibson RA. Cytokines (IL-1β, IL-6, TNF-α, TGF-β1, and TGF-β2) and Prostaglandin E2 in Human Milk during the First Three Months Postpartum. Pediatr Res. 1999;46:194–199. doi: 10.1203/00006450-199908000-00012. PubMed DOI

Hackett RJ, Davis LS, Lipsky PE. Comparative effects of tumor necrosis factor-alpha and IL-1 beta on mitogen-induced T cell activation. J Immunol. 1988;140:2639–2644. doi: 10.4049/jimmunol.140.8.2639. PubMed DOI

Sabbaj S, Edwards BH, Ghosh MK, Semrau K, Cheelo S, Thea DM, Kuhn L, et al. Human Immunodeficiency Virus-Specific CD8(+) T Cells in Human Breast Milk. J Virol. 2002;76:7365–7373. doi: 10.1128/JVI.76.15.7365-7373.2002. PubMed DOI PMC

Tatematsu M, Takahashi M, Tsuda H, Hirose M, Furihata C, Sugimura T. Precocious differentiation of immature chief cells in fundic mucosa of infant rats induced by hydrocortisone. Cell Differ. 1975;4:285–294. doi: 10.1016/0045-6039(75)90013-5. PubMed DOI

Ma LJ, Walter B, DeGuzman A, Muller HK, Walker AM. Trans-Epithelial Immune Cell Transfer during Suckling Modulates Delayed-Type Hypersensitivity in Recipients as a Function of Gender. PLoS One. 2008;3:e3562. doi: 10.1371/journal.pone.0003562. PubMed DOI PMC

Tuboly S, Bernáth S. Intestinal Absorption of Colostral Lymphoid Cells in Newborn Animals. Adv Exp Med Biol. 2002;503:107–114. doi: 10.1007/978-1-4615-0559-4_12. PubMed DOI

Rose EC, Odle J, Blikslager AT, Ziegler AL. Probiotics, Prebiotics and Epithelial Tight Junctions: A Promising Approach to Modulate Intestinal Barrier Function. Int J Mol Sci. 2021;22:6729. doi: 10.3390/ijms22136729. PubMed DOI PMC

Catassi C, Bonucci A, Coppa GV, Carlucci A, Giorgi PL. Intestinal Permeability. Changes during the First Month: Effect of Natural versus Artificial Feeding. J Pediatr Gastroenterol Nutr. 1995;21:383–386. doi: 10.1002/j.1536-4801.1995.tb11955.x. PubMed DOI

Roux ME, McWilliams M, Phillips-Quagliata JM, Weisz-Carrington P, Lamm ME. Origin of IgA-secreting plasma cells in the mammary gland. J Exp Med. 1977;146:1311–1322. doi: 10.1084/jem.146.5.1311. PubMed DOI PMC

Rose ML, Parrott DM, Bruce RG. The accumulation of immunoblasts in extravascular tissues including mammary gland, peritoneal cavity, gut and skin. Immunology. 1978;35:415–423. PubMed PMC

Ramanan D, Sefik E, Galván-Peña S, Wu M, Yang L, Yang Z, Kostic A, et al. An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint. Cell. 2020;181:1276–1290.e13. doi: 10.1016/j.cell.2020.04.030. PubMed DOI PMC

Ghosh MK, Nguyen V, Muller HK, Walker AM. Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus. J Immunol. 2016;197:2290–2296. doi: 10.4049/jimmunol.1502483. PubMed DOI PMC

Tanneau GM, Oyant LHS, Chevaleyre CC, Salmon HP. Differential Recruitment of T- and IgA B-lymphocytes in the Developing Mammary Gland in Relation to Homing Receptors and Vascular Addressins. J Histochem Cytochem. 1999;47:1581–1592. doi: 10.1177/002215549904701210. PubMed DOI

Lokossou GAG, Kouakanou L, Schumacher A, Zenclussen AC. Human Breast Milk: From Food to Active Immune Response With Disease Protection in Infants and Mothers. Front Immunol. 2022;13:849012. doi: 10.3389/fimmu.2022.849012. PubMed DOI PMC

Li S, Zhang L, Zhou Q, Jiang S, Yang Y, Cao Y. Characterization of Stem Cells and Immune Cells in Preterm and Term Mother's Milk. J Hum Lact. 2019;35:528–534. doi: 10.1177/0890334419838986. PubMed DOI

Fan Y, Chong YS, Choolani MA, Cregan MD, Chan JKY. Unravelling the Mystery of Stem/Progenitor Cells in Human Breast Milk. PLoS One. 2010;5:e14421. doi: 10.1371/journal.pone.0014421. PubMed DOI PMC

Handgretinger R, Kuçi S. CD133-Positive Hematopoietic Stem Cells: From Biology to Medicine. Adv Exp Med Biol. 2013;777:99–111. doi: 10.1007/978-1-4614-5894-4_7. PubMed DOI

Hassiotou F, Beltran A, Chetwynd E, Stuebe AM, Twigger A-J, Metzger P, Trengove N, et al. Breastmilk Is a Novel Source of Stem Cells with Multilineage Differentiation Potential. Stem Cells. 2012;30:2164–2174. doi: 10.1002/stem.1188. PubMed DOI PMC

Chappert P, Schwartz RH. Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol. 2010;22:552–559. doi: 10.1016/j.coi.2010.08.005. PubMed DOI PMC

Chappert P, Leboeuf M, Rameau P, Lalfer M, Desbois S, Liblau RS, Danos O, et al. Antigen-specific Treg impair CD8 + T-cell priming by blocking early T-cell expansion. Eur J Immunol. 2010;40:339–350. doi: 10.1002/eji.200839107. PubMed DOI

Carter AM. Animal models of human pregnancy and placentation: alternatives to the mouse. Reproduction. 2020;160:R129–R143. doi: 10.1530/REP-20-0354. PubMed DOI