PU.1 regulates TCR expression by modulating GATA-3 activity
Open accessAbstract
The Ets transcription factor PU.1 is a master regulator for the development of multiple lineages during hematopoiesis. The expression pattern of PU.1 is dynamically regulated during early T lineage development in the thymus. We previously revealed that PU.1 delineates heterogeneity of effector Th2 populations. In this study, we further define the function of PU.1 on the Th2 phenotype using mice that specifically lack PU.1 in T cells using an lck-Cre transgene with a conditional Sfpi1 allele (Sfpi1(lck-/-)). Although deletion of PU.1 by the lck-Cre transgene does not affect T cell development, Sfpi1(lck-/-) T cells have a lower activation threshold than wild-type T cells. When TCR engagement is limiting, Sfpi1(lck-/-) T cells cultured in Th2 polarizing conditions secrete higher levels of Th2 cytokines and have greater cytokine homogeneity than wild-type cells. We show that PU.1 modulates the levels of TCR expression in CD4(+) T cells by regulating the DNA-binding activity of GATA-3 and limiting GATA-3 regulation of TCR gene expression. GATA-3-dependent regulation of TCR expression is also observed in Th1 and Th2 cells. In CD4(+) T cells, PU.1 expression segregates into subpopulations of cells that have lower levels of surface TCR, suggesting that PU.1 contributes to the heterogeneity of TCR expression. Thus, we have identified a mechanism whereby increased GATA-3 function in the absence of the antagonizing activity of PU.1 leads to increased TCR expression, a reduced activation threshold, and increased homogeneity in Th2 populations.
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PU.1 regulates TCR expression by modulating GATA-3 activity, decreasing the threshold of activation.
“we have shown that it regulates the expression of TCR in T cells, decreasing the threshold of activation [15].”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [15]
The Discussion says PU.1 regulates TCR expression by modulating GATA-3, but it gives the opposite direction for the activation threshold: CD4 T cells expressing PU.1 have a higher threshold. It is PU.1 deficiency that the paper associates with a reduced threshold (Discussion, passages 7 and 3; page numbers not provided). (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPU.1-deficient Th9 cells given control retrovirus show fewer IL-9-secreting cells, less IL-9 production, and more IL-4 production than wild-type Th9 cells.
“PU.1-deficient Th9 cells transduced with control retrovirus had significantly reduced IL-9-secreting cells and IL-9 production compared to wild-type Th9 cells, and increased production of IL-4, as previously described (Chang et al, 2009) (Fig. 2C–E).”
From Gcn5 Is Required for PU.1-Dependent IL-9 Induction in Th9 Cells (2012) · cites this paper as Chang et al, 2009
The Results section on T-cell signaling and Th2 cytokine production reports higher cytokine secretion from PU.1-deficient Th2 cultures than from wild-type cultures, which offers limited support for the IL-4 comparison. The cited paper does not report the claimed Th9 control-retrovirus comparison or measurements of IL-9-secreting cells and IL-9 production; its retroviral-transduction methods describe Th1 and Th2 cells instead. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPU.1 functions, at least in part, by limiting the ability of GATA-3 and IRF4 to interact with cytokine loci targets.
“PU.1 functions, at least in part, by limiting the ability of GATA-3 and IRF4 to interact with cytokine loci targets7–9.”
From The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation (2010) · cites this paper as [7]
The Results section reports that PU.1 limits GATA-3 binding to the Il4 enhancer, supporting the GATA-3 portion of the claim. The paper does not establish that PU.1 also limits IRF4 interaction with cytokine loci. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDecreasing PU.1 expression or PU.1-deficiency increases overall cytokine production specifically in populations of cells that secrete two or more cytokines.
“while shRNA that decreased PU.1 expression, or PU.1-deficiency, increased overall cytokine production specifically in populations of cells that secreted two or more cytokines7,8.”
From The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation (2010) · cites this paper as [7]
The Results section (page not provided) reports higher secreted Th2 cytokine levels and more double-cytokine-producing cells after PU.1 deficiency under suboptimal anti-CD3 stimulation; it also reports that shRNA reduction of PU.1 increased the number of cells producing two Th2 cytokines. The increase was not specific to cells producing two or more cytokines: IL-5 single-positive cells also increased, and double-positive frequencies were similar under optimal stimulation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEctopic expression of PU.1 reduces production of most TH2 cytokines.
“Ectopic expression of PU.1 reduced production of most TH2 cytokines”
From The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation (2010) · cites this paper as [7]
The Results section reports higher Th2 cytokine secretion from PU.1-deficient cells than from wild-type cells when TCR stimulation was limiting. It also reports that ectopic PU.1 expression decreased Tcra mRNA, but does not show that ectopic expression reduced production of most Th2 cytokines. The claim therefore captures PU.1’s inhibitory role but attributes the cytokine result to a different experiment. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Lck-Cre-mediated deletion of the Sfpi1 allele in γδ T cell populations is at least 50% complete.
“Although deletion was not complete as previously observed in double-positive thymocytes [15], there was at least 50% deletion in γδ T cell populations (Fig. 2A).”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [15]
The Results section (page unavailable) says Lck-Cre-mediated Sfpi1 deletion begins at the DN3 stage and is not complete until later in thymocyte development. It does not report a deletion percentage for γδ T cells. In the citing sentence, the citation follows the statement about incomplete deletion; the at-least-50% figure is attributed to the citing paper’s Fig. 2A. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPU.1 is specifically expressed in subpopulations of TH2 cells that have low IL-4 expression.
“PU.1 was specifically expressed in subpopulations of TH2 cells that had low IL-4 expression.”
From The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation (2010) · cites this paper as [7]
αβ T cell development and numbers in various lymphoid organs are unaltered by PU.1-deficiency.
“Flow cytometry of splenocytes and thymocytes showed similar profiles of CD3+ αβTCR and CD3+ NKT cells between wild-type and Sfpi1 lck−/− mice (Fig. 1A).”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [15]
PU.1 appears to have distinct effects in various types of T cells: negatively regulating γδ T cell numbers, negatively regulating Th2 cytokine production and TCR expression, while promoting IL-9 expression.
“Thus, PU.1 appears to have distinct effects in various types of T cells, negatively regulating γδ T cell numbers, negatively regulating Th2 cytokine production and TCR expression, while promoting IL-9 expression [15]–[17].”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [15]
PU.1 limits expression of Th2 cytokines and contributes to Th2 heterogeneity.
“We have also demonstrated that PU.1 limits the expression of Th2 cytokines and contributes to Th2 heterogeneity [15], [16].”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [15]
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- Authors
- Chang, H.-C., Han, L., Jabeen, R., Carotta, S., Nutt, S. L., & Kaplan, M. H.
- Affiliations
- Department of Pediatrics, Herman B Wells Center for Pediatric Research
- Walter and Eliza Hall Institute of Medical Research (AU)
- Indiana University Indianapolis (US)
- Corresponding author
- Han, Ling
- Jabeen, Rukhsana
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-10
- Volume
- 183
- Issue
- 8
- Pages
- 4887-4894
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2768261
- OpenAlex
- W2124457673
- Cited by
- 66
- References
- 34
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 11 · 2012: 4
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service
- National Institute of Allergy and Infectious Diseases (AI057459, R01AI057459)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, GATA3, T cell receptor expression, Th2 cells, Th1 cells, T cell activation threshold, T cell differentiation, transcriptional regulation, CD4+ T cells, ETS transcription factors
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Female, Mice, Inbred C57BL, Mice, Transgenic, Proto-Oncogene Proteins, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, Trans-Activators, Cytokines, Th2 Cells, RNA, Small Interfering, GATA3 Transcription Factor, Mice, Gene Knockdown Techniques
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