Solt, L. | Search bioRxiv

bioRxiv2026

Selective Glucocorticoid Receptor Modulators of Immune Checkpoint Function

Glucocorticoids (GCs) coordinate immunity, inflammation, and metabolism through allosteric regulation of the glucocorticoid receptor (GR) transcription factor. GCs are indispensable anti-inflammatory drugs yet linking specific ligand-receptor structural states to specific biological outcomes has remained a major barrier to designing safer, more selective therapies. Using structure-based design, we developed selective glucocorticoid receptor modulators (SGRMs) of immune function by extending a steroidal scaffold from the ligand-binding pocket into an adjacent solvent channel. These SGRMs suppressed T cell pro-inflammatory cytokines and promoted differentiation of memory precursor T cells while showing minimal induction of M2 macrophage polarization or T cell checkpoint proteins PD-1 and CTLA-4, all key targets of immunotherapy. Molecular dynamics simulations revealed that solvent-channel substituents function as a lever arm to drive dynamic oscillations in the steroid core, thereby allosterically tuning GR activity states. Systematic perturbation of immune cells with a graded series of ligands enabled a ligand perturbation with machine learning (LPML) framework to map coregulated responses across cell types and identified effector T cell gene networks tightly coupled with immune checkpoint induction. This approach outlines a general strategy for decoding the logic of allosteric drug action, enabling the rational design of SGRMs with tailored immunomodulatory profiles.

systems biology↗

bioRxiv2026

Negative regulation of TH17-mediated inflammation by the nuclear receptor REV-ERBβ

TH17 cells play a central role in several human autoimmune diseases. We and others reported the nuclear receptor, REV-ERB, as a cell-intrinsic repressor of TH17-mediated pathogenicity. REV-ERB{beta}, REV-ERBs closely related family member, is thought to be functionally redundant to REV-ERB, which we sought to explore in TH17-mediated immunity. Our data indicate that deletion of REV-ERB{beta} enhances TH17-mediated pro-inflammatory cytokine expression and exacerbated disease in mouse models of multiple sclerosis and colitis. RNA-sequencing indicates REV-ERB{beta} and REV-ERB do not have similar transcriptional profiles. REV-ERB{beta} does not appear to regulate gene expression through interaction with the classic co-repressor NCoR1, which is in contrast to REV-ERB in TH17 cells, nor does it utilize heme, its known endogenous ligand for its repressive functions. Our results establish that while REV-ERB{beta} also acts as a negative regulator of TH17-cell function and pathogenicity, it does so in a manner that is non-redundant, independent, and unique to REV-ERB.

immunology↗