# Control of B cell differentiation by IFNg induced transcription factors

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $259,967

## Abstract

Up to 20% of all individuals in the US are treated for an autoimmune and/or chronic inflammatory disease.
Autoimmune diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are responsible
for significant suffering and represent an enormous financial burden to the health care system. Despite the
release of new therapies, many individuals remain refractory to treatment. Thus, there is still a very large unmet
need to develop new medicines that can be used to treat autoimmune patients. Although we know that B cells,
B lineage antibody (Ab) secreting cells (ASCs) and inflammatory cytokines all play important roles in driving
clinical disease, we still lack a fundamental understanding of how acute or chronic inflammatory signals initiate
commitment of B cells into the ASC lineage and whether B cells contribute to pathology only through their
production of Abs or whether inflammatory effector B cells also contribute to immunity or immunopathology. We
identified a unique population of circulating T-bethi pre-ASCs (DN2 cells) that are expanded in a subset of SLE
and RA patients. We showed that these cells, which have also been observed in other autoimmune and chronic
inflammatory settings, are associated with increased systemic inflammatory cytokines, pathogenic autoAbs and
disease severity. We identified the inflammatory cytokine IFNg as key inducer of the T-bethi pre-ASC subset. We
further showed that IFNg signals significantly enhance development of both mouse and human ASCs and
determined that two IFNg-induced transcription factors (TFs), T-bet and IRF1, play important but distinct roles in
IFNg-induced ASC development. In this application we are testing our central hypothesis that IFNg induces two
mutually exclusive or competing cell fate programs in B cells – a cytokine-producing effector cell fate and an
ASC differentiation fate – and that integration of signals from TLRs and other cytokines, like IL-2, cooperate with
T-bet to repress the inflammatory fate and promote IRF1-mediated differentiation into ASCs. The immediate
objectives of this proposal are to (i) determine how IFNg signals synergize with TLR, IL-2 and IL-21 to promote
human ASC development and (ii) determine whether the balance between IRF1 and T-bet regulates the
development of protective or damaging immune B cell mediated humoral and inflammatory responses in the
setting of viral infection and autoimmunity. Our long-term goal is to use what we learn about how B cell fate
decisions are programmed to identify interventions that can be that can prevent the formation, maintenance or
function of potentially pathogenic B cell subsets. This research is significant because we will for the first time
define at a molecular level how IFNg contributes to human B cell fate decisions and how two of the TFs induced
by IFNg, T-bet and IRF1, cooperate to facilitate ASC development in the settings of acute infectious and chronic
autoimmune disease. We expect that these studie...

## Key facts

- **NIH application ID:** 10070568
- **Project number:** 5R01AI110508-07
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Frances E. Lund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $259,967
- **Award type:** 5
- **Project period:** 2014-02-14 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070568

## Citation

> US National Institutes of Health, RePORTER application 10070568, Control of B cell differentiation by IFNg induced transcription factors (5R01AI110508-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070568. Licensed CC0.

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