Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages
Open accessAbstract
The involvement of small heterodimer partner (SHP) in the inhibition of hepatic bile acid synthesis from cholesterol has been established. However, extrahepatic expression of SHP implies that SHP may have regulatory functions other than those in the liver. Here, we find that SHP mRNA expression is high in murine bone marrow cells, suggesting a physiological role within macrophages. Indeed, expression of SHP in macrophages decreases the transcriptional activity and nuclear localization of nuclear factor κB, whereas downregulation of SHP has the opposite effects. Expression of genes associated with macrophage-T cell crosstalk were altered by overexpression or downregulation of SHP. Intriguingly, increasing SHP expression in macrophages resulted in decreased T cell expansion, a hallmark of T cell activation, whereas knockdown of SHP resulted in increased expansion. Analyses of the expanded T cells revealed a dichotomous skewing between effector T cells and regulatory T cells (Tregs), with SHP overexpression reducing Tregs and downregulation of SHP increasing their expansion. The expanded Tregs were confirmed to be suppressive via adoptive transfers. IL-2 and TGF-β, known inducers of Treg differentiation, were found to be regulated by SHP. Furthermore, SHP occupancy at the promoter region of IL-2 was increased after macrophages were challenged with lipopolysaccharide. Neutralizing antibodies to IL-2 and TGF-β inhibited the expansion of Tregs mediated by downregulation of SHP. Thi…
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NR0B2 suppresses several aspects of the inflammasome in myeloid cells, resulting in decreased expansion of regulatory T cells.
“The negative regulator of cholesterol catabolism, NR0B2, was found to suppress several aspects of the inflammasome in myeloid cells, resulting in decreased expansion of regulatory T cells (Tregs) (24, 25).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [24]
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- Authors
- Shahoei, S. H., Kim, Y.-C., Cler, S. J., Ma, L., Anakk, S., Kemper, J. K., & Nelson, E. R.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Nelson, Erik R
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2019-05-03
- Volume
- 160
- Issue
- 7
- Pages
- 1573-1589
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC6549582
- OpenAlex
- W2942522116
- Cited by
- 16
- References
- 57
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R00CA172357, R01CA234025)
- U.S. Department of Defense (BC171214)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK62777, DK95842, DK113080)
- American Heart Association (16SDG27570006)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- small heterodimer partner, macrophages, T cell expansion, regulatory T cells, effector T cells, NF-κB, interleukin-2, TGF-beta, Treg differentiation, lipopolysaccharide, autoimmune disease, cancer immunotherapy
- MeSH terms
- Animals, Bone Marrow Cells, Cell Line, Gene Expression Regulation, Macrophages, T-Lymphocytes, Down-Regulation, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Cell Proliferation, Mice
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