# Proinflammatory B Cells Defined by TIM-4 in the Alloimmune Response

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $677,724

## Abstract

B cells play important Ab-independent roles either promoting or regulating immune responses through the
opposing activity of regulatory B cells (Bregs) and proinflammatory effector B cells (Beff). B cell depletion with
anti-CD20 can rapidly improve autoimmune diseases such as RA and MS, without depleting auto-Ab. Yet, peri-
transplant B cell depletion can markedly increase renal allograft rejection and chronic vasculopathy in heart
transplants. These contradictory results are likely due to the presence of both Bregs and Beff, and not knowing
which predominates at a given time, in a given clinical setting, or in a given patient. A similar dichotomy is present
in mice, where B cell depletion/deficiency can either inhibit or promote autoimmunity and allograft rejection. We
contend that targeting B cells in autoimmune and transplant patients would have greater efficacy if Beff and
Bregs could be selectively targeted. Unfortunately, until the advent of Tim-1, there was no unifying marker for
Bregs, hampering understanding of their biology. Even less was known about Beff cells. In mice, B cells
expressing pro-inflammatory cytokines such as IL-6 and IFN play a key role promoting autoimmune responses
in EAE and proteoglycan-induced arthritis. Moreover, in response to various infections, B cells exhibit rapid
innate-like protective responses through expression of TNF, IFN, IL-2, and IL-17. However, it is unknown
whether, or how, any of these responses relate to one another, because no phenotype for Beff was established
and individual cytokines were examined in isolation. Thus, major aspects of Beff biology, including what regulates
their induction and cytokine expression, and relationship to Bregs, if any, were completely unknown. We
discovered that Tim-4 identifies Beff that express IFN and accelerate allograft and tumor rejection. We have
now used RNAseq and quantitative PCR to demonstrate that Tim-4+ Beff express a pro-inflammatory module
that includes IL-17a, IL-17f, IL-22, GM-CSF, IL-6, and IL-1 - all driven by IL-23 signaling. RORt-driven IL-17
not only reinforces its own expression, but is essential to enforce the proinflammatory module, and prevent
dysregulated expression of IL-10 and potent Breg function. While IL-23 inhibits IL-10 expression by Tim-1+ Bregs,
it does not induce inflammatory cytokines. Thus, Tim-4 is a unifying marker for Beffs and we are now in a prime
position to further identify signaling pathways and transcription factors (TF) that control their induction and
cytokine expression, and at the same time counter-regulate regulatory molecule expression.
 In Aim 1 we will further define the Tim-4+ Beff transcriptome and pathways that regulate the Beff inflammatory
module and counter-regulate Breg activity. In Aim 2, we will identify TFs that regulate the Tim-4+ Beff
inflammatory module. In Aim 3 we will define the in vivo mechanisms of Tim-4+ Beff activity in transplantation by
defining the roles of antigen specificity, plasma...

## Key facts

- **NIH application ID:** 10942289
- **Project number:** 1R01AI184980-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** DAVID M ROTHSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $677,724
- **Award type:** 1
- **Project period:** 2024-06-17 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942289

## Citation

> US National Institutes of Health, RePORTER application 10942289, Proinflammatory B Cells Defined by TIM-4 in the Alloimmune Response (1R01AI184980-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10942289. Licensed CC0.

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