# T cell regulation of pathogenic B cells in systemic autoimmunity

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $452,576

## Abstract

Abstract
Systemic lupus erythematosus (lupus) is characterized by polyclonal B cell activation, leading to the production
of pathogenic class-switched autoantibodies that promote tissue injury. These B cells undergo somatic mutation
and immunoglobulin isotype switching in extrafollicular (EF) sites and germinal centers (GCs) located within
secondary lymphoid organs, sites of CD4+ T cell-dependent B cell maturation. Mounting evidence suggests that
in lupus, autoantibody-producing B cells such as memory B cells, CD11c+Tbet+ B cells, and plasma cells are
generated via both EF and GC reactions. Yet, the contribution of each of these B cell subsets to the generation
and activity of autoantibodies in lupus remain unclear. CD11c+Tbet+ B cells (Tbet+ B cells herein) are a distinct
B cell subset that differentiate following viral infections as well as autoimmunity in mice and humans. Emerging
studies have shown that in murine and human lupus, Tbet+ B cells are critical drivers of pathogenic
autoantibodies. In lupus, Tbet+ B cells are capable of differentiating into class-switched autoantibody-secreting
cells upon stimulation by cytokines and TLR agonists. The presence of Tbet+ B cells in severe disease has been
well elucidated, but their development and contribution as disease progresses in lupus is poorly understood. We
found that the kinetics of Tbet+ B cell development and expansion in lupus-prone mice mirror the increase of
autoantibodies and worsening disease state. Moreover, we show a temporal loss of the GC-derived Tbet+ B cell
population coinciding with their expansion in the blood as disease progresses. We previously demonstrated that
Tbet+ B cells arise predominantly independent of GCs during viral infections, and our preliminary data show that
Tbet+ B cells appear to be mainly, but not exclusively, from EFs in lupus-prone mice as well. Tbet+ B cell
development in requires IFN- a subset of CD4+ T helper cells, T follicular helper (Tfh)
cells. These cytokines are secreted by Tfh cells throughout disease promoting pathogenic Tbet+ B cell
responses. We found that CD9 expression on Tfh cells identifies the IL-21 and IFN-γ secreting subset, which we
found to expanded in mice and human lupus. Our overarching hypothesis is Tbet+ B cells that arise from EF or
γ and IL-21 signaling from
GCs are transcriptionally and functionally distinct, but in lupus the chronic inflammatory milieu in different tissues
leads to their aberrant regulation and differentiation into ASCs that contribute to disease. Accordingly, we will
explore temporal changes in genetic regulation that functionally impact pathogenic Tbet+ B cell development
from EF or GCs and from tissues such as the kidney in autoimmune disease. We will use unique transgenic
lupus mice, combined with cellular techniques and novel genomic approaches to investigate the genetic
regulation influencing function of these B cells at different stages of disease. We will also examine the
requirement for the CD9-exp...

## Key facts

- **NIH application ID:** 10812554
- **Project number:** 2R01AR073912-06A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Jason Weinstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $452,576
- **Award type:** 2
- **Project period:** 2024-02-23 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812554

## Citation

> US National Institutes of Health, RePORTER application 10812554, T cell regulation of pathogenic B cells in systemic autoimmunity (2R01AR073912-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10812554. Licensed CC0.

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