Abstract
The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.
| Original language | English |
|---|---|
| Pages (from-to) | 3394-3409.e20 |
| Journal | Cell |
| Volume | 184 |
| Issue number | 13 |
| DOIs | |
| State | Published - 24 Jun 2021 |
Bibliographical note
Funding Information:We thank Dr. Catherine Donner (Department of Obstetrics and Gynecology, Hôpital Erasme, University Libre de Bruxelles (ULB), Bruxelles, Belgium) for helping with the precious fetal blood samples. We also thank the Electron Microscopy Unit, National University of Singapore, particularly Tan Suat Hoon and Lu Thong Beng. We thank all the members of the Ginhoux laboratory for helpful discussions. Flow cytometry and cell sorting, CyTOF, microscopy, and RNA library preparation were carried out on SIgN platforms established by the Agency of Science, Technology and Research (A ∗ STAR) Singapore. SIgN platforms are supported by a BMRC grant ( IAF311006 ) and BMRC transition funds ( H16/99/b0/011 ). F.G. is supported by EMBO YIP , Singapore Immunology Network core funding (A ∗ STAR), and a Singapore NRF Senior Investigatorship ( NRFI2017-02 ). S.A. is supported by the National Research Foundation Singapore under its NMRC Centre Grant Programme ( NMRC/CG/M003/2017 ) and administered by the Singapore Ministry of Health’s National Medical Research Council. This study received other grant support from NMRC ( NMRC/TA/0059/201 , NMRC/MOHIAFCAT2/005/2015 , NMRC/TCR/0015-NCC/2016 , NMRC/OFLCG/002/2018 , MH095:003\016-0002 , MH095:003\016-001 , NMRC/STaR19nov-0002 , and CIRG19may0052 ), Duke-NUS , Singhealth AMC , and core funding. J.K.Y.C. is supported by NMRC ( CIRG/1484/2018 and NMRC CSA (SI)/008/2016 ). N.M is funded by the Wellcome Trust and Royal Society ( 204464/Z/16/Z ) and BMRC YIG ( 1618251041 ). A.M. is supported by HFSP LTF postdoctoral fellowship, 2019 ( LT000363/2019-L ). T.T.A. is supported by NUSMed postdoctoral fellowship ( NUHSRO/2019/046/PDF/19 ). B.M. was funded by NUHS start-up grant ( NUHSRO/2018/006/SU/01 ) and core funds from SIgN/A ∗ STAR .
Funding Information:
We thank Dr. Catherine Donner (Department of Obstetrics and Gynecology, H?pital Erasme, University Libre de Bruxelles (ULB), Bruxelles, Belgium) for helping with the precious fetal blood samples. We also thank the Electron Microscopy Unit, National University of Singapore, particularly Tan Suat Hoon and Lu Thong Beng. We thank all the members of the Ginhoux laboratory for helpful discussions. Flow cytometry and cell sorting, CyTOF, microscopy, and RNA library preparation were carried out on SIgN platforms established by the Agency of Science, Technology and Research (A?STAR) Singapore. SIgN platforms are supported by a BMRC grant (IAF311006) and BMRC transition funds (H16/99/b0/011). F.G. is supported by EMBO YIP, Singapore Immunology Network core funding (A?STAR), and a Singapore NRF Senior Investigatorship (NRFI2017-02). S.A. is supported by the National Research Foundation Singapore under its NMRC Centre Grant Programme (NMRC/CG/M003/2017) and administered by the Singapore Ministry of Health's National Medical Research Council. This study received other grant support from NMRC (NMRC/TA/0059/201, NMRC/MOHIAFCAT2/005/2015, NMRC/TCR/0015-NCC/2016, NMRC/OFLCG/002/2018, MH095:003\016-0002, MH095:003\016-001, NMRC/STaR19nov-0002, and CIRG19may0052), Duke-NUS, Singhealth AMC, and core funding. J.K.Y.C. is supported by NMRC (CIRG/1484/2018 and NMRC CSA (SI)/008/2016). N.M is funded by the Wellcome Trust and Royal Society (204464/Z/16/Z) and BMRC YIG (1618251041). A.M. is supported by HFSP LTF postdoctoral fellowship, 2019 (LT000363/2019-L). T.T.A. is supported by NUSMed postdoctoral fellowship (NUHSRO/2019/046/PDF/19). B.M. was funded by NUHS start-up grant (NUHSRO/2018/006/SU/01) and core funds from SIgN/A?STAR. Conceptualization, A.M. G.C.L. N.M. S.A. J.K.Y.C. and F.G.; methodology, A.M. G.C.L. N.M. S.A. J.K.Y.C. and F.G.; investigation, A.M. G.C.L. L.J.Y. N.M. S.A. J.K.Y.C. and F.G.; formal analysis, A.M. G.C.L. L.J.Y. B.M. N.M. and F.G.; data curation, A.M. G.C.L. L.J.Y. T.T.A. R.P. A. Shanti, and N.M.; writing, A.M. G.C.L. L.J.Y. N.M. S.A. J.K.Y.C. and F.G.; visualization, A.M. G.C.L. L.J.Y. B.M. N.M. and F.G.; resources, N.S. A.R.-M. E.S. G.S.N.S. R.P. A. Sharma, R.M.M.W. A.L. C.K. C.A.D. S.C. K.G.S, N.B.S. X.-M.Z. S.K. F.C. A.S.M.T. G.L. P.C. Y.F. P.X.H. A.K.M.L. M.C. D.V. A. Sharma, G.F. R.S. N.P. and B.M.; funding acquisition, A.M. N.M. S.A. J.K.Y.C. and F.G.; supervision, S.A. J.K.Y.C. and F.G. The authors declare no competing interests.
Publisher Copyright:
© 2021
Keywords
- Tem
- Treg
- bacteria
- fetal Development
- fetal immunity
- immune memory
- immune priming
- microbes
- microbiome