Upadacitinib Restrains the Pathogenic Fitness of CD4⁺ T Cells and Aberrant B Cell Programming in Optic Neuritis.

Authors

Gengchen Jiang, Qi Jiang, Lian Han, Yue Peng, Xingyu Liu, Tong Yang, Hao Huang, Jiaying Liu, Yuan Gao, Hui Yang, Wenjun Zou, Zhaohuai Li, Wenru Su

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77701. Sep 09, 2026. Epub Sep 09, 2026.

Abstract

Optic neuritis (ON) is a neuroinflammatory autoimmune disease harboring autoreactive lymphocytes. Effector memory CD4⁺ T cells (CD4⁺ T_em) represent a prominently expanded and pro-inflammatory subset within this compartment, yet their pathogenic metabolic programs remain poorly defined. B cell dysfunction also contributes to ON pathogenesis. However, whether T cell-intrinsic metabolic rewiring directly fuels this B cell dysregulation awaits elucidation. Here, through single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from ON patients, we conceptualized a pathological circuit linking T cell metabolic reprogramming to aberrant T-B crosstalk. In pathogenic CD4⁺ T_em, JAK1 upregulation and enhanced STAT3 phosphorylation propagated a metabolic rewiring transcriptional program and secured T cell fitness via MCL1 induction. An inferred cholesterol export signature distinguished this subset and engaged the nuclear sensor RORA on B cells to instruct pro-inflammatory polarization and humoral commitment. In turn, subverted B cells perpetuated exaggerated antigen presentation and cytokine secretion, cementing pathogenic CD4⁺ T_em differentiation and sustaining a self-amplifying inflammatory loop. Cross-disease profiling extended this axis to allied autoimmune disorders. Selective JAK1 blockade with upadacitinib (UPA) restored immune homeostasis and attenuated experimental autoimmune encephalomyelitis (EAE), phenocopied by MCL1 inhibition. Together, these findings nominate UPA as a targeted therapy for ON and allied autoimmune disorders.

PMID:
42717487
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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