Advisor(s)

Frances Lund

Committee Member(s)

Christopher Scharer
Jianmei Leavenworth
John Kearney
Paul Goepfert

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Microbiology

Abstract

Interferon regulatory factor 1 (IRF1), encoded within the 5q31 locus harboring variants associated with systemic lupus erythematosus (SLE), links interferons (IFN) and Toll-like receptor (TLR) signals to lymphocyte programs, yet its role in B cells and SLE, a disease driven by IFN-induced dysregulated B cell responses, is unclear. Using a TLR7-driven lupus mouse model, single-cell multi-omics, human SLE samples, and genetic perturbations in primary human B cells, we show that IRF1 regulates the transcriptome and epigenome of B cells to drive IFN-stimulated, proliferation, and secretory/stress modules that collectively enforce pathogenic B cell identity. IRF1 loss prevents activation of these programs, redirects B cell trajectories toward germinal center (GC) and resting-like memory B cell (MBC) fates, reduces disease-associated pathology, and extends survival. Mechanistically, IRF1 regulates chromatin accessibility at the Irf4 locus, thereby controlling the Irf4–Irf8 balance in antibody-secreting cell (ASC) precursors. B cells from human SLE patients converge on altered IRF1–IRF4 coupling, linking genetic risk at the IRF1 locus to pathogenic B cell circuitry in human disease. Beyond lupus, we identify IRF1 as a B cell-intrinsic licensing transcription factor that couples BCR and innate signals to the Notch program required for marginal zone B cell (MZB) lineage commitment in C57BL/6J (B6) mice. BCR and TLR4 stimulation induces IRF1 upregulation and nuclear localization in immature MZB precursors, and IRF1 is required for Notch2-dependent target gene induction following DLL1 engagement to enable acquisition of MZB identity. To define how IRF1 shapes B cell composition during aging, we longitudinally profiled B cell subsets in aging B6 wild-type and B6.Irf1-/- mice. IRF1 loss imposes persistent remodeling of the aging B cell compartment, including reduced MZB, age-associated B cells (ABC), ASC generation, and altered GC B cell and class-switched IgG MBC dynamics. IRF1 deficiency also blunts age-linked kidney pathology, lowers proteinuria, and mitigates hallmark histopathologic features of age-associated renal injury. Together, these findings position IRF1 as a rheostat coupling IFN and TLR sensing to B cell fate decisions, providing a unifying framework for inflammatory transcriptional control in autoimmunity and inflammaging and nominating IRF1-centered pathways as tractable therapeutic nodes.

Keywords

B cells;Inflammaging;IRF1;IRF4;IRF8;Systemic lupus erythematosus

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Available for download on Monday, May 29, 2028

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