Differential Expression of PU.1 and Key T Lineage Transcription Factors Distinguishes Fetal and Adult T Cell Development
Open accessAbstract
The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by Spi1, during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the Spi1 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of Spi1 compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ETPs derived from first-wave precursors naturally express lower levels of PU.1 than adult ETPs, but are almost unchanged in their ability to generate early fetal T cells when PU.1 is reduced still further (~5 fold) by deletion of the major upstream regulatory element of PU.1.
“ETPs derived from these precursors naturally express lower levels of PU.1 than adult ETPs, but they are almost unchanged in their ability to generate early fetal T cells when the level of PU.1 is reduced still further (~5 fold) by deletion of the major upstream regulatory element of PU.1 (147).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe same five-fold diminished level of PU.1 sharply degrades the ability of later fetal hematopoietic stem and progenitor cells to generate T cells at all, in vivo or in vitro, with functional and phenotypic defects evident in mutants in both multipotent progenitors and newly-entered intrathymic ETPs, as early as in the late fetus.
“In contrast, the same five-fold diminished level of PU.1 sharply degrades the ability of later fetal hematopoietic stem and progenitor cells to generate T cells at all, in vivo or in vitro, with functional and phenotypic defects evident in the mutants in both multipotent progenitors and newly-entered intrathymic ETPs, as early as in the late fetus.”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredFor many first-wave fetal thymocytes, PU.1 activity may last only a day or two, and is mostly or entirely dispensable.
“In contrast, for many first-wave fetal thymocytes it may last only a day or two, and is mostly or entirely dispensable (71, 147).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
The Discussion (page unavailable) says the early fetal T-cell developmental wave is largely PU.1 independent, supporting the claim’s qualified dispensability point. The study used mice with reduced, not absent, PU.1 expression, and our copy does not establish that PU.1 activity lasts only a day or two in first-wave fetal thymocytes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe change in PU.1's role occurs within fetal life, situated in the transition from precociously committed first-wave precursors to precursors that enter the thymus while still multipotent.
“In the case of PU.1, the change in its role occurs within fetal life, and this has now been sharply situated in the transition from precociously committed “first-wave” precursors to precursors that enter the thymus while still multipotent (147).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
These differences conspicuously include reduced initial expression of multiple PU.1-dependent genes in the fetal cells.
“Montecino-Rodriguez et al. point out that these differences conspicuously include reduced initial expression of multiple PU.1-dependent genes in the fetal cells (147).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
PU.1 activity probably extends for over 10 days for thymocytes in young adult mice, where it is crucial for successful T-cell generation.
“It probably extends for over 10 days for the thymocytes in young adult mice (153), where it is crucial for successful T-cell generation (2, 147).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [147]
PU.1 confers an inflammatory phenotype to B cells and macrophages.
“By initiating the expression of pro-inflammatory cytokines, PU.1 confers an inflammatory phenotype to B cells and macrophages [12,13,14].”
From Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release (2024) · cites this paper as [13]
The Introduction describes PU.1’s role in T-cell regulatory genes, and the Discussion discusses its regulation of CD127 expression. Neither addresses pro-inflammatory cytokine production or an inflammatory phenotype in B cells or macrophages. Searches for those cell types, cytokines, and inflammation found no supporting passage in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589 · see citing works
Ikuta, K., Kina, T., MacNeil, I., Uchida, N., Peault, B., Chien, Y.-H., & Weissman, I. L. (1990) · Cell · doi:10.1016/0092-8674(90)90262-d · Cited by 583 · see citing works
Thymopoiesis independent of common lymphoid progenitors.
Allman, D., Sambandam, A., Kim, S., Miller, J. P., Pagan, A., Well, D., Meraz, A., & Bhandoola, A. (2003) · Nature Immunology · doi:10.1038/ni878 · Cited by 544 · see citing works
Zhang, J. A., Mortazavi, A., Williams, B. A., Wold, B. J., & Rothenberg, E. V. (2012) · Cell · doi:10.1016/j.cell.2012.01.056 · Cited by 337 · see citing works
Carotta, S., Dakic, A., D'Amico, A., Pang, S. H. M., Greig, K. T., Nutt, S. L., & Wu, L. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.005 · Cited by 279 · see citing works
Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
Kueh, H. Y., Champhekar, A., Nutt, S. L., Elowitz, M. B., & Rothenberg, E. V. (2013) · Science · doi:10.1126/science.1240831 · Cited by 273 · see citing works
Effects of Aging on the Common Lymphoid Progenitor to Pro-B Cell Transition
Min, H., Montecino-Rodriguez, E., & Dorshkind, K. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.2.1007 · Cited by 126 · see citing works
Self-citationPrethymic T‐cell development defined by the expression of paired immunoglobulin‐like receptors
Masuda, K., Kubagawa, H., Ikawa, T., Chen, C., Kakugawa, K., Hattori, M., Kageyama, R., Cooper, M. D., Minato, N., Katsura, Y., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600878 · Cited by 79 · see citing works
Champhekar, A., Damle, S. S., Freedman, G., Carotta, S., Nutt, S. L., & Rothenberg, E. V. (2015) · Genes & Development · doi:10.1101/gad.259879.115 · Cited by 74 · see citing works
Zarnegar, M. A., Chen, J., & Rothenberg, E. V. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00354-10 · Cited by 52 · see citing works
Belyaev, N. N., Biró, J., Athanasakis, D., Fernandez-Reyes, D., & Potocnik, A. J. (2012) · Immunogenetics · doi:10.1007/s00251-012-0620-6 · Cited by 24 · see citing works
Flagged first, then by citations
Research works printed but not linked: 33
- [1]Rothenberg E Moore J Yui M 2008 Launching the T-cell-lineage developmental programme Nat Rev Immunol 8 9 21 18097446 PMC3131407
- [2]Bhandoola A von Boehmer H Petrie H Zuniga-Flucker J 2007 Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from Immunity 26 678 689 17582341
- [3]Petrie H Zuniga-Pflucker J 2007 Zoned out: functional mapping of stromal signaling microenvironments in the thymus Annu Rev Immunol 25 649 679 17291187
- [5]Chien Y Meyer C Bonneville M 2014 gd T cells: first line of defense and beyond Annu Rev Immunol 32 121 155 24387714
- [6]Luc S Luis T Boukarabila H Macaulay I Buza-Vidas N Bouriez-Jones T Lutteropp M Woll P Loughran S Mead A Hultquist A Brown J Mizukami T Matsuoka S Ferry H Anderson K Duarte S Atkinson D Soneji S Domanski A Farley A Sanjuan-Pla A Carella C Patient R de Bruijn M Enver T Nerlov C Blackburn C Godin I Jacobsen S 2012 The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential Nat Immunol 13 412 419 22344248 PMC3378629
- [7]Yoshimoto M Porayette P Glosson N Conway S Carlesso N Cardoso A Kaplan M Yoder M 2012 Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence Blood 119 5706 5714 22431573 PMC3382930
- [8]Böiers C Carrelha J Lutteropp M Luc S Green J Azzoni E Woll P Mead A Hultquist A Swiers G Perdiguero E MI Melchiori L Luis TKS Bouriez-Jones T Deng Q Pontén A Atkinson D Jensen C Sitnicka E Geissmann F Godin I Sandberg R de Bruijn M Jacobsen S 2013 Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells Cell Stem Cell 13 535 548 24054998
- [9]Ramond C Berthault C Burlen-Defranoux O de Sousa A Guy-Grand D Vieira P Pereira P Cumano A 2013 Two waves of distinct hematopoietic progenitor cells colonize the fetal thymus Nat Immunol 15 27 35 24317038
- [11]Havran W Allison J 1990 Origin of Thy1+ dendritic epidermal cells of adult mice from fetal thymic precursors Nature 344 68 70 1968230
- [12]Crompton T Outram S Buckland J Owen M 1998 Distinct roles of the interleukin-7 receptor alpha chain in fetal and adult thymocyte development revealed by analysis of interleukin-7 receptor alpha -deficient mice Eur J Immunol 28 1859 1866 9645367
- [13]Hosokawa H Rothenberg E 2017 Cytokines, transcription factors, and the initiation of T-cell development Cold Spring Harb Perspect Biol 10.1101/cshperspect.a028621 PMC5876153 28716889 · DOI
- [14]Watanabe Y Aiba Y Katsura Y 1997 T cell progenitors in the murine fetal liver: Differences from those in the adult bone marrow Cell Immunol 177 18 25 9140092
- [15]Schilham M Wilson A Moere R Benaissa-Trouw B Cumano A Clevers H 1998 Critical involvement of Tcf-1 in expansion of thymocytes J Immunol 161 3984 3991 9780167
- [16]Wang JH Nichogiannopouloua A Wub L Suna L Sharpe A Bigby M Georgopoulos K 1996 Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation Immunity 5 537 549 8986714
- [19]Spain L Guerriero A Kunjibettu S Scott E 1999 T cell development in PU.1-deficient mice J Immunol 163 2681 2687 10453009
- [20]Rosenbauer F Owens B Yu L Tumang J Steidl U Kutok J Clayton L Wagner K Scheller M Iwasaki H Liu C Hackanson B Akashi K Leutz A Rothstein T Plass C Tenen D 2006 Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1 Nat Genet 38 27 37 16311598
- [21]Scott E Simon M Anastasi J Singh H 1994 Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages Science 265 1573 1577 8079170
- [22]McKercher S Torbett B Anderson K Henkel G Vestal D Baribault H Klemsz M Feeney A Wu G Paige C Maki R 1996 Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities EMBO J 15 5647 5658 8896458 PMC452309
- [24]Herzenberg LA Herzenberg L 1989 Toward a layered immune system Cell 59 953 954 2688900
- [26]Montecino-Rodriguez E Leathers H Dorshkind K 2006 Identification of a B-1 B cell-specified progenitor Nat Immunol 7 293 301 16429139
- [27]Ramsdell F Zúñiga-Pflücker J Takahama Y 2001 In Vitro Systems for the Study of T Cell Development: Fetal Thymus Organ Culture and OP9-DL1 Cell Coculture Current Protocols in Immunology John Wiley & Sons, Inc 18432973
- [28]Manning J Mitchell B Appadurai D Shakya A Pierce L Wang H Nganga V Swanson P May J Tantin D Spangrude G 2013 Vitamin C promotes maturation of T-cells Antioxid Redox Signal 19 2054 2067 23249337 PMC3869442
- [29]Owen J Ritter M 1969 Tissue interaction in the development of thymus lymphocytes J exp Med 129 431 442 5762051 PMC2138610
- [30]Montecino-Rodriquez E Fice M Casero D Barber C Berent-Maoz B Dorshkind K 2016 Distinct genetic programs orchestrate the emergence of distinct waves of B1 and B-2 progenitor development Immunity 45 527 533 27566938 PMC5033716
- [31]Pernit C Vasseur F 1989 Cell proliferation and differentiation in the fetal and early postnatal mouse thymus J Immunol 142 3369 3377 2785552
- [32]Staber P Zhan G Ye M Welne R Nombela-Arrieta C Bach C Kerenyi M Bartholdy B Zhang H Alberich-Jordà M Lee S Yang H Ng F Zhang J Leddin M Silberstein L Hoefler G Orkin S Göttgens B Rosenbauer F Huang G Tenen D 2013 Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells Mol Cell 49 934 946 23395001 PMC3644723
- [33]Porritt HE Rumfelt LL Tabrizifard S Schmitt TM Zúñiga-Pflücker JC Petrie HT 2004 Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages Immunity 20 735 745 15189738
- [34]Min H Montecino-Rodriguez E Dorshkind K 2004 Reduction in the developmental potential of intrathymic T cell progenitors with age The Journal of Immunology 173 245 15210781
- [36]Sambandam A Maillard I Zediak V Xu L Gerstein R Aster J Pear W Bhandoola A 2005 Notch signaling controls the generation and differentiation of early T lineage progenitors Nat Immunol 6 663 670 15951813
- [39]Jotereau F Le Douarin N 1982 Demonstration of a cyclic renewal of the lymphocyte precursor cells in the embryonic chick thymus J Immunol 129 1869 1877 7119436
- [40]Coltey M Jotereau F Le Douarin N 1987 Evidence for a cyclic renewal of lymphocye precursor cells in the embryonic chick thymuis Cell Differ 22 71 82 3690675
- [43]DeKoter RP Schweitzer BL Kamath MB Jones D Tagoh H Bonifer C Hildeman DA Huang KJ 2007 Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells Journal of Biological Chemistry 282 14194 14204 17392277 PMC4222673
- [44]Xue HH Bollenbacher J Rovella V Tripuraneni R Du YB Liu CY Williams A McCoy JP Leonard WJ 2004 GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells Nature Immunology 5 1036 15361867
Cited by
Sorted by citations
Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development
Rothenberg, E. V., Hosokawa, H., & Ungerbäck, J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00228 · Cited by 99 · see citing works
“1-dependent genes in the fetal cells (147).”
BackgroundInfluentialHarrer, D. C., Eder, M., Barden, M., Pan, H., Herr, W., & Abken, H. (2024) · Cancers · doi:10.3390/cancers16152737 · Cited by 1 · see citing works
- Authors
- Montecino-Rodriguez, E., Casero, D., Fice, M., Le, J., & Dorshkind, K.
- Affiliations
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California , Los Angeles, CA 90095
- University of California, Los Angeles (US)
- Corresponding author
- Dorshkind, Kenneth
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03
- Volume
- 200
- Issue
- 6
- Pages
- 2046-2056
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC5840016
- OpenAlex
- W2785322585
- Cited by
- 17
- References
- 11
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 1
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (AI28697, AI021256, CA16042)
- National Cancer Institute (P30CA016042)
- National Institute of Allergy and Infectious Diseases (R37AI021256, R01AI021256, P30AI028697)
- Jonsson Comprehensive Cancer Center
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, T cell development, thymopoiesis, T cell differentiation, transcriptional regulation
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Fetus, Mice, Inbred C57BL, Proto-Oncogene Proteins, T-Lymphocytes, Transcription Factors, Trans-Activators, Gene Expression, Cell Lineage, Mice, Precursor Cells, T-Lymphoid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
