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.
N1 - Financial Support: This work was supported by grants to E.R.N. from the National Cancer Institute of the National Institutes of Health (R00CA172357, R01CA234025) and from the Department of Defense Breast Cancer Research Program (BC171214). This study was also supported in part by an American Heart Association scientist development award (16SDG27570006) to Y.-C.K. and grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01DK62777 and R01DK95842 to J.K.K., and R01DK113080 to S.A.).
PY - 2019
Y1 - 2019
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.
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U2 - 10.1210/en.2019-00025
DO - 10.1210/en.2019-00025
M3 - Article
C2 - 31050726
AN - SCOPUS:85067375298
SN - 0013-7227
VL - 160
SP - 1573
EP - 1589
JO - Endocrinology
JF - Endocrinology
IS - 7
ER -