# Role of Tim-l in B Cells in regulating autoimmunity in the CNS

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $631,364

## Abstract

PROJECT SUMMARY
Accumulating evidence supports that B cell can regulate immune responses and are essential for limiting
inflammation and autoimmunity by IL-10-dependent and -independent mechanisms. The processes and
mechanisms by which B cells with regulatory properties are generated have also not been identified. We have
shown that Tim-1 is also expressed on B cells that produce IL-10 and Tim-1 is required for apoptotic cell (AC)
binding to B cells and induction of IL-10. We generated a mouse with a conditional deletion of Tim-1 selectively
on B cells (Tim-1BKO). The Tim-1BKO mice show progressive loss of IL-10 production in B cells and, with age,
developed severe multi-organ tissue inflammation including colitis, dermatitis, hepatitis and a paralytic disease
with meningeal inflammation in the CNS. On the other hand, Tim-1BKO mice show strong anti-tumor immunity
with inhibition of tumor growth. Therefore, in addition to serving as a marker for regulatory function of B cells,
Tim-1 as a phosphatidylserine receptor is also functionally required for optimal regulatory B cell function.
However, it is not clear what induces Tim-1 expression and what are the transcription factors that drive Tim-1
expression and regulatory B cell function. Our data clearly shows that Tim-1 does not define a subset of B cells
but can be induced on B cell upon activation. Based on the preliminary data we hypothesize that Tim-1 is a
functional marker on B cells that can induce IL-10 upon binding to AC and regulate tissue inflammation,
autoimmunity, and anti-tumor immunity. To address this hypothesis we propose to: 1) Identify Transcriptional
Regulators of Tim-1+ B cells, focusing on EHF as the positive regulator of Tim-1, which was identified by a
focused Crispr-Cas9 screen; 2) Study the effect of loss of Tim-1 on B cells in generating pro-inflammatory
effector B cells, as Tim-1BKO B cells are highly activated and produce proinflammatory cytokines including IL-23
and IL-6 which promote differentiation of pathogenic Th17 cells; 3) Study the role of Tim-1+ B cells in maintaining
stem-like Th17 cells and limit differentiation of pathogenic CXCR6+ Th17 cells. We have found that Tim-1+ B
cells produce Wnt10a, which promotes stemness, and other suppressive cytokines that keep Th17 cells in a
stem-like state and limit their differentiation into pathogenic Th17 cells. The proposed studies will greatly increase
our understanding of the role of Tim-1 in B cells and the generation of regulatory activity on B cells to promote
immune tolerance and limit tissue inflammation and autoimmunity. These studies will provide a novel therapeutic
strategy by targeting B cells for the treatment of autoimmune diseases and promoting anti-tumor immunity.

## Key facts

- **NIH application ID:** 10943323
- **Project number:** 1R01AI185514-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $631,364
- **Award type:** 1
- **Project period:** 2024-06-21 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943323

## Citation

> US National Institutes of Health, RePORTER application 10943323, Role of Tim-l in B Cells in regulating autoimmunity in the CNS (1R01AI185514-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10943323. Licensed CC0.

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