Mapping the developing human immune system across organs

Abstract

Single-cell genomics studies have decoded the immune cell composition of several human prenatal organs but were limited in describing the developing immune system as a distributed network across tissues. We profiled nine prenatal tissues combining single-cell RNA sequencing, antigen-receptor sequencing, and spatial transcriptomics to reconstruct the developing human immune system. This revealed the late acquisition of immune-effector functions by myeloid and lymphoid cell subsets and the maturation of monocytes and T cells before peripheral tissue seeding. Moreover, we uncovered system-wide blood and immune cell development beyond primary hematopoietic organs, characterized human prenatal B1 cells, and shed light on the origin of unconventional T cells. Our atlas provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine, and disease understanding.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 103

1. 1.

   Park J-E, Jardine L, Gottgens B, Teichmann SA, Haniffa M. Prenatal development of human immunity. Science. 2020;368:600-603.

   Not in our library10.1126/science.aaz9330

2. 2.

   Jagannathan-Bogdan M, Zon LI. Hematopoiesis. Dev Camb Engl. 2013;140:2463-2467.

   Not in our library10.1242/dev.083147

3. 3.

   Popescu D-M, et al. Decoding human fetal liver haematopoiesis. Nature. 2019;574:365-371.

   Not in our library10.1038/s41586-019-1652-y

4. 4.

   Stewart BJ, et al. Spatiotemporal immune zonation of the human kidney. Science. 2019;365:1461-1466.

   Not in our library10.1126/science.aat5031

5. 5.
   Tracing the first hematopoietic stem cell generation in human embryo by single-cell RNA sequencing · 2019

   No notice
6. 6.

   Zeng Y, et al. Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos. Immunity. 2019;51:930-948.

   Not in our library10.1016/j.immuni.2019.09.008

7. 7.

   Park J-E, et al. A cell atlas of human thymic development defines T cell repertoire formation. Science. 2020;367.

   Not in our library10.1126/science.aay3224

8. 8.
   Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn’s Disease · 2020

   No notice
9. 9.

   Cao J, et al. A human cell atlas of fetal gene expression. Science. 2020;370.

   Not in our library10.1126/science.aba7721

10. 10.

    Reynolds G, et al. Developmental cell programs are co-opted in inflammatory skin disease. Science. 2021;371:eaba6500.

    Not in our library10.1126/science.aba6500

11. 11.

    Jardine L, et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature. 2021;1-5.

    Not in our library10.1038/s41586-021-03929-x

12. 12.

    Lopez R, Regier J, Cole MB, Jordan MI, Yosef N. Deep generative modeling for single-cell transcriptomics. Nat Methods. 2018;15:1053-1058.

    Not in our library10.1038/s41592-018-0229-2

13. 13.
    A comprehensive single cell transcriptional landscape of human hematopoietic progenitors · 2019

    No notice
14. 14.

    Villani A-C, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017;356:eaah4573.

    Not in our library10.1126/science.aah4573

15. 15.
    Mapping single-cell data to reference atlases by transfer learning · 2021

    No notice
16. 16.

    Kleshchevnikov V, et al. Cell2location maps fine-grained cell types in spatial transcriptomics. Nat Biotechnol. 2022;1-11.

    Not in our library10.1038/s41587-021-01139-4

17. 17.

    Chong SZ, et al. CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses. J Exp Med. 2016;213:2293-2314.

    Not in our library10.1084/jem.20160800

18. 18.
    Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations · 2018

    No notice
19. 19.
    Transcriptional profiling of microglia; current state of the art and future perspectives · 2019

    No notice
20. 20.

    Toor SM, Wani S, Albagha OME, et al. Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs. Front Genet. 2021;12.

    Not in our library10.3389/fgene.2021.781272

21. 21.
    Cross-tissue immune cell analysis reveals tissue-specific features in humans · 2022

    No notice
22. 22.

    Dann E, Henderson NC, Teichmann SA, Morgan MD, Marioni JC. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat Biotechnol. 2021;1-9.

    Not in our library10.1038/s41587-021-01033-z

23. 23.

    Jeucken KCM, Koning JJ, Mebius RE, Tas SW. The Role of Endothelial Cells and TNF-Receptor Superfamily Members in Lymphoid Organogenesis and Function During Health and Inflammation. Front Immunol. 2019;10:2700.

    Not in our library10.3389/fimmu.2019.02700

24. 24.

    Yang X, et al. Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression. Int J Cancer. 2006;118:1869-1876.

    Not in our library10.1002/ijc.21596

25. 25.

    Hua F, Tian Y. CCL4 promotes the cell proliferation, invasion and migration of endometrial carcinoma by targeting the VEGF-A signal pathway. Int J Clin Exp Pathol. 2017;10:11288-11299.

    Not in our library

26. 26.

    Keeley EC, Mehrad B, Strieter RM. CXC chemokines in cancer angiogenesis and metastases. Adv Cancer Res. 2010;106:91-111.

    Not in our library10.1016/s0065-230x(10)06003-3

27. 27.

    Heidemann J, et al. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem. 2003;278:8508-8515.

    Not in our library10.1074/jbc.m208231200

28. 28.

    Norrby K. Mast cells and angiogenesis. APMIS Acta Pathol Microbiol Immunol Scand. 2002;110:355-371.

    Not in our library10.1034/j.1600-0463.2002.100501.x

29. 29.

    Ribatti D, Crivellato E. The role of mast cell in tissue morphogenesis. Thymus, duodenum, and mammary gland as examples. Exp Cell Res. 2016;341:105-109.

    Not in our library10.1016/j.yexcr.2015.11.022

30. 30.

    Wood W, Martin P. Macrophage Functions in Tissue Patterning and Disease: New Insights from the Fly. Dev Cell. 2017;40:221-233.

    Not in our library10.1016/j.devcel.2017.01.001

31. 31.

    Hoorweg K, Cupedo T. Development of human lymph nodes and Peyer's patches. Semin Immunol. 2008;20:164-170.

    Not in our library10.1016/j.smim.2008.02.003

32. 32.

    Rantakari P, et al. Fetal liver endothelium regulates the seeding of tissue-resident macrophages. Nature. 2016;538:392-396.

    Not in our library10.1038/nature19814

33. 33.

    Li N, et al. Memory CD4+ T cells are generated in the human fetal intestine. Nat Immunol. 2019;20:301-312.

    Not in our library10.1038/s41590-018-0294-9

34. 34.
    Microbial exposure during early human development primes fetal immune cells · 2021

    No notice
35. 35.

    Xing Y, Wang X, Jameson SC, Hogquist KA. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling. Nat Immunol. 2016;17:565-573.

    Not in our library10.1038/ni.3419

36. 36.

    Webb LV, Ley SC, Seddon B. TNF activation of NF-κB is essential for development of single-positive thymocytes. J Exp Med. 2016;213:1399-1407.

    Not in our library10.1084/jem.20151604

37. 37.

    Collins C, Sharpe E, Silber A, Kulke S, Hsieh EWY. Congenital Athymia: Genetic Etiologies, Clinical Manifestations, Diagnosis, and Treatment. J Clin Immunol. 2021;41:881-895.

    Not in our library10.1007/s10875-021-01059-7

38. 38.

    Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy. 2000;55:688-697.

    Not in our library10.1034/j.1398-9995.2000.00118.x

39. 39.

    Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70−. J Exp Med. 2011;208:67-80.

    Not in our library10.1084/jem.20101499

40. 40.

    Griffin D, Rothstein T. Human B1 Cell Frequency: Isolation and Analysis of Human B1 Cells. Front Immunol. 2012;3:122.

    Not in our library10.3389/fimmu.2012.00122

41. 41.

    Rothstein TL, Griffin DO, Holodick NE, Quach TD, Kaku H. Human B-1 cells take the stage. Ann NY Acad Sci. 2013;1285:97-114.

    Not in our library10.1111/nyas.12137

42. 42.

    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11:34-46.

    Not in our library10.1038/nri2901

43. 43.

    Lalor PA, Herzenberg LA, Adams S, Stall AM. Feedback regulation of murine Ly-1 B cell development. Eur J Immunol. 1989;19:507-513.

    Not in our library10.1002/eji.1830190315

44. 44.

    Hayakawa K, Hardy RR, Parks DR, Herzenberg LA. The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med. 1983;157:202-218.

    Not in our library10.1084/jem.157.1.202

45. 45.

    Montecino-Rodriguez E, Dorshkind K. B-1 B Cell Development in the Fetus and Adult. Immunity. 2012;36:13-21.

    Not in our library10.1016/j.immuni.2011.11.017

46. 46.

    Kantor AB, Merrill CE, Herzenberg LA, Hillson JL. An unbiased analysis of V(H)-D-J(H) sequences from B-1a, B-1b, and conventional B cells. J Immunol Baltim Md 1950. 1997;158:1175-1186.

    Not in our library

47. 47.

    Tornberg UC, Holmberg D. B-1a, B-1b and B-2 B cells display unique VHDJH repertoires formed at different stages of ontogeny and under different selection pressures. EMBO J. 1995;14:1680-1689.

    Not in our library10.1002/j.1460-2075.1995.tb07157.x

48. 48.

    Miyama-Inaba M, et al. Unusual phenotype of B cells in the thymus of normal mice. J Exp Med. 1988;168:811-816.

    Not in our library10.1084/jem.168.2.811

49. 49.
    Cells of the human intestinal tract mapped across space and time · 2021

    No notice
50. 50.

    Schulze-Luehrmann J, Ghosh S. Antigen-receptor signaling to nuclear factor kappa B. Immunity. 2006;25:701-715.

    Not in our library10.1016/j.immuni.2006.10.010

51. 51.

    Alonzo ES, Sant’Angelo DB. Development of PLZF-expressing innate T cells. Curr Opin Immunol. 2011;23:220-227.

    Not in our library10.1016/j.coi.2010.12.016

52. 52.

    Dimova T, et al. Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire. Proc Natl Acad Sci. 2015;112:E556-E565.

    Not in our library10.1073/pnas.1412058112

53. 53.

    Tan L, et al. A fetal wave of human type 3 effector γδ cells with restricted TCR diversity persists into adulthood. Sci Immunol. 2021;6:eabf0125.

    Not in our library10.1126/sciimmunol.abf0125

54. 54.

    Mayassi T, Barreiro LB, Rossjohn J, Jabri B. A multilayered immune system through the lens of unconventional T cells. Nature. 2021;595:501-510.

    Not in our library10.1038/s41586-021-03578-0

55. 55.

    Carico ZM, Roy Choudhury K, Zhang B, Zhuang Y, Krangel MS. Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire. Cell Rep. 2017;19:2157-2173.

    Not in our library10.1016/j.celrep.2017.05.045

56. 56.

    Lee YJ, et al. Generation of PLZF+ CD4+ T cells via MHC class II-dependent thymocyte–thymocyte interaction is a physiological process in humans. J Exp Med. 2010;207:237-246.

    Not in our library10.1084/jem.20091519

57. 57.

    Cho H, Bediako Y, Xu H, Choi H-J, Wang C-R. Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells. Proc Natl Acad Sci. 2011;108:13241-13246.

    Not in our library10.1073/pnas.1105118108

58. 58.

    Georgiev H, Peng C, Huggins MA, Jameson SC, Hogquist KA. Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells. Nat Commun. 2021;12:2308.

    Not in our library10.1038/s41467-021-22589-z

59. 59.

    Hoffman ES, et al. Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. Genes Dev. 1996;10:948-962.

    Not in our library10.1101/gad.10.8.948

60. 60.

    Spits H. Development of αβ T cells in the human thymus. Nat Rev Immunol. 2002;2:760-772.

    Not in our library10.1038/nri913

61. 61.

    Montel-Hagen A, et al. Organoid-induced differentiation of conventional T cells from human pluripotent stem cells. Cell Stem Cell. 2019;24:376-389.

    Not in our library10.1016/j.stem.2018.12.011

62. 62.

    Mass E, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353:aaf4238.

    Not in our library10.1126/science.aaf4238

63. 63.

    Mende N, Laurenti E. Hematopoietic stem and progenitor cells outside the bone marrow: where, when, and why. Exp Hematol. 2021;104:9-16.

    Not in our library10.1016/j.exphem.2021.10.002

64. 64.

    Mende N, et al. Blood.

    Not in our library10.1182/blood.2021013450

65. 65.

    Krishnan S, et al. Hematopoietic stem and progenitor cells are present in healthy gingiva tissue. J Exp Med. 2021;218:e20200737.

    Not in our library10.1084/jem.20200737

66. 66.

    Kim H. Homeostatic and pathogenic extramedullary hematopoiesis. J Blood Med. 2010;1:13-19.

    Not in our library10.2147/jbm.s7224

67. 67.

    Brioschi S, et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021;373:eabf9277.

    Not in our library10.1126/science.abf9277

68. 68.

    Schafflick D, et al. Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges. Nat Neurosci. 2021;24:1225-1234.

    Not in our library10.1038/s41593-021-00880-y

69. 69.

    Wang Y, et al. Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges. Immunity. 2021;54:2784-2794.

    Not in our library10.1016/j.immuni.2021.09.016

70. 70.

    Montecino-Rodriguez E, Leathers H, Dorshkind K. Identification of a B-1 B cell–specified progenitor. Nat Immunol. 2006;7:293-301.

    Not in our library10.1038/ni1301

71. 71.

    Esplin BL, Welner RS, Zhang Q, Borghesi LA, Kincade PW. A differentiation pathway for B1 cells in adult bone marrow. Proc Natl Acad Sci. 2009;106:5773-5778.

    Not in our library10.1073/pnas.0811632106

72. 72.

    Yoshimoto M, et al. Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc Natl Acad Sci U S A. 2011;108:1468-1473.

    Not in our library10.1073/pnas.1015841108

73. 73.

    Kreslavsky T, Wong JB, Fischer M, Skok JA, Busslinger M. Control of B-1a cell development by instructive BCR signaling. Curr Opin Immunol. 2018;51:24-31.

    Not in our library10.1016/j.coi.2018.01.001

74. 74.

    Graf R, et al. BCR-dependent lineage plasticity in mature B cells. Science. 2019;363:748-753.

    Not in our library10.1126/science.aau8475

75. 75.

    Mimitou EP, et al. Multiplexed detection of proteins, transcriptomes, clonotypes and CRISPR perturbations in single cells. Nat Methods. 2019;16:409-412.

    Not in our library10.1038/s41592-019-0392-0

76. 76.

    Fleming SJ, Marioni JC, Babadi M. CellBender remove-background: a deep generative model for unsupervised removal of background noise from scRNA-seq datasets. 2019;791699.

    Not in our library

77. 77.

    Wolock SL, Lopez R, Klein AM. Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Syst. 2019;8:281-291.

    Not in our library10.1016/j.cels.2018.11.005

78. 78.

    Heaton H, et al. Souporcell: robust clustering of single-cell RNA-seq data by genotype without reference genotypes. Nat Methods. 2020;17:615-620.

    Not in our library10.1038/s41592-020-0820-1

79. 79.
    SCANPY: large-scale single-cell gene expression data analysis · 2018

    No notice
80. 80.

    Gayoso A, et al. A Python library for probabilistic analysis of single-cell omics data. Nat Biotechnol. 2022;40:163-166.

    Not in our library10.1038/s41587-021-01206-w

81. 81.

    Pedregosa F, et al. Scikit-learn: Machine Learning in Python. J Mach Learn Res. 2011;12:2825-2830.

    Not in our library

82. 82.
    From Louvain to Leiden: guaranteeing well-connected communities · 2019

    No notice
83. 83.
    BBKNN: fast batch alignment of single cell transcriptomes · 2019

    No notice
84. 84.
    Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool · 2013

    No notice
85. 85.
    glmGamPoi: fitting Gamma-Poisson generalized linear models on single cell count data · 2020

    No notice
86. 86.
    Confronting false discoveries in single-cell differential expression · 2021

    No notice
87. 87.

    Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139-140.

    Not in our library10.1093/bioinformatics/btp616

88. 88.
    Scirpy: a Scanpy extension for analyzing single-cell T-cell receptor-sequencing data · 2020

    No notice
89. 89.
    Single-cell multi-omics analysis of the immune response in COVID-19 · 2021

    No notice
90. 90.

    Gupta NT, et al. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics. 2015;31:3356-3358.

    Not in our library10.1093/bioinformatics/btv359

91. 91.
    Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data · 2020

    No notice
92. 92.

    Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R. CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat Protoc. 2020;15:1484-1506.

    Not in our library10.1038/s41596-020-0292-x

93. 93.
    Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro · 2021

    Corrected
94. 94.

    Setty M, et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat Biotechnol. 2019;37:451-460.

    Not in our library10.1038/s41587-019-0068-4

95. 95.
    CellRank for directed single-cell fate mapping · 2022

    No notice
96. 96.

    Park J-E, Teichmann S, Haniffa M, Taghon T. Collection of codes and annotated matrix for the paper “A cell atlas of human thymic development defines T cell repertoire formation”. 2021.

    Not in our library10.5281/zenodo.5500511

97. 97.
    Squidpy: a scalable framework for spatial omics analysis · 2022

    No notice
98. 98.

    Virshup I, Rybakov S, Theis FJ, Angerer P, Wolf FA. anndata: Annotated data. 2021;2021.12.16.473007.

    Not in our library10.1101/2021.12.16.473007

99. 99.

    Dann E, Suo C, Goh I, Kleshchevnikov V. Teichlab/Pan_fetal_immune: Analysis code for publication. 2022.

    Not in our library10.5281/zenodo.6481461

100. 100.

     Dick SA, et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles. Sci Immunol. 2022;7:eabf7777.

     Not in our library10.1126/sciimmunol.abf7777

101. 101.

     Gadala-Maria D, Yaari G, Uduman M, Kleinstein SH. Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles. Proc Natl Acad Sci. 2015;112:E862-E870.

     Not in our library10.1073/pnas.1417683112

102. 102.

     Egawa T, et al. The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity. 2001;15:323-334.

     Not in our library10.1016/s1074-7613(01)00185-6

103. 103.

     Nagasawa T, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635-638.

     Not in our library10.1038/382635a0

Cited by papers we hold 7

• Human SARS-CoV-2 challenge uncovers local and systemic response dynamics · 2024
  Corrected
• BANKSY unifies cell typing and tissue domain segmentation for scalable spatial omics data analysis · 2024
  No notice
• An integrated cell atlas of the lung in health and disease · 2023
  No notice
• The Evolution of Single-Cell RNA Sequencing Technology and Application: Progress and Perspectives · 2023
  No notice
• Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota · 2022
  No notice
• RNA modifications: importance in immune cell biology and related diseases · 2022
  No notice
• Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease · 2022
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.