AUTHOR=Koetzier Steven C. , van Langelaar Jamie , Wierenga-Wolf Annet F. , Melief Marie-José , Pol Kim , Musters Suzanne , Lubberts Erik , Dik Willem A. , Smolders Joost , van Luijn Marvin M. 

TITLE=Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.893702

DOI=10.3389/fimmu.2022.893702

ISSN=1664-3224

ABSTRACT=<p>In early multiple sclerosis (MS), an IFN-γ<sup>high</sup>GM-CSF<sup>high</sup>IL-17<sup>low</sup> CD4<sup>+</sup> T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)<sub>2</sub>D<sub>3</sub>), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)<sub>2</sub>D<sub>3</sub> than Th17 cells, as reflected by lower vitamin D receptor (<italic>VDR</italic>) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)<sub>2</sub>D<sub>3</sub> exposure. Upon T-cell activation, <italic>VDR</italic> levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)<sub>2</sub>D<sub>3</sub>-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. In activated Th17.1 cells, 1,25(OH)<sub>2</sub>D<sub>3</sub> amplified the suppressive effects of methylprednisolone (MP) on proliferation, MDR1 surface levels, secretion of IFN-γ and granzyme B, as well as expression of brain-homing markers CCR6 and VLA-4. The addition of P4 to 1,25(OH)<sub>2</sub>D<sub>3</sub> further enhanced MP-mediated reduction in proliferation, CD25, CCR6 and CXCR3. Overall, this study indicates that glucocorticoid sensitivity of Th17.1 cells can be enhanced by treatment with 1,25(OH)<sub>2</sub>D<sub>3</sub> and further improved with P4. Our observations implicate steroid hormone crosstalk as a therapeutic avenue in Th17.1-associated inflammatory diseases including MS.</p>