Abstract
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. This study demonstrates that expression and activity of SHP within macrophages can alter T cell fate and identifies SHP as a potential therapeutic target for autoimmune diseases or solid cancers.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1573-1589 |
| Number of pages | 17 |
| Journal | Endocrinology |
| Volume | 160 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Endocrinology
Cite this
Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages. / Shahoei, Sayyed Hamed; Kim, Young Chae; Cler, Samuel J.; Ma, Liqian; Anakk, Sayeepriyadarshini; Kemper, Jongsook K.; Nelson, Erik R.
In: Endocrinology, Vol. 160, No. 7, 01.01.2019, p. 1573-1589.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages
AU - Shahoei, Sayyed Hamed
AU - Kim, Young Chae
AU - Cler, Samuel J.
AU - Ma, Liqian
AU - Anakk, Sayeepriyadarshini
AU - Kemper, Jongsook K.
AU - Nelson, Erik R.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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. This study demonstrates that expression and activity of SHP within macrophages can alter T cell fate and identifies SHP as a potential therapeutic target for autoimmune diseases or solid cancers.
AB - 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. This study demonstrates that expression and activity of SHP within macrophages can alter T cell fate and identifies SHP as a potential therapeutic target for autoimmune diseases or solid cancers.
UR - http://www.scopus.com/inward/record.url?scp=85067375298&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067375298&partnerID=8YFLogxK
U2 - 10.1210/en.2019-00025
DO - 10.1210/en.2019-00025
M3 - Article
C2 - 31050726
AN - SCOPUS:85067375298
VL - 160
SP - 1573
EP - 1589
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 7
ER -