# Role of Tim-1 and Bregs in Tolerance and Autoimmunity

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $492,250

## Abstract

PROJECT SUMMARY
Accumulating evidence supports that regulatory B cells (Bregs), are essential for limiting inflammation and
autoimmunity by IL-10-dependent and -independent manners. The lack of a universal marker for identifying
Bregs, however, has hampered our understanding of their critical biologic functions. The processes and
mechanisms by which Bregs are generated have also not been identified. Dr. Rothstein’s lab as well as our
own have shown that Tim-1 identifies IL-10-producing Bregs. We have generated a mouse with loss of function
Tim-1 mutant (Tim-1∆mucin), and found that both Tim-1∆mucin and traditional Tim-1 deficient (Tim-1-/-) show
progressive loss of IL-10 production in B cells. Additionally, with age, these mice developed severe multi-organ
tissue inflammation. We have recently demonstrated that Tim-1 on Bregs is required for apoptotic cell (AC)
binding to Bregs and for AC-induced IL-10 production in Bregs. B cells from both mice are unable to produce
IL-10 in response to AC. Thus, we hypothesis that Tim-1 is also critical and essential for optimal Breg function
in maintaining immune tolerance and limiting inflammatory responses by sensing AC, which will be addressed
in Aim 1 by using Tim-1 floxed mice we recently generated. In addition to producing IL-10, our RNA-seq
analysis have demonstrated that Tim-1+ Bregs also express many other inhibitory molecules, some of which
have been shown to regulate IL-10-independent Breg function. We have also demonstrated that some
inhibitory molecules regulate IL-10 in Tim-1+ Bregs. Therefore, we hypothesize that Tim-1+ Bregs exert their
regulatory function not only by producing IL-10, but also by expressing a panel of inhibitory molecules, which
give Bregs the optimal ability to suppress autoimmune responses—this will be examined in Aim 2. Our RNA-
seq dataset identified a set of transcription factors differentially expressed in Tim-1+ Bregs. Thus, we propose
to study the role of the transcription factors in Bregs in Aim 3. These studies will greatly increase our
understanding of the role of Tim-1 in Bregs and the role of Bregs in immune tolerance and autoimmunity, and
may also provide a novel therapeutic strategy by targeting B cells for the treatment of autoimmune diseases.
!

## Key facts

- **NIH application ID:** 10214479
- **Project number:** 5P01AI129880-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $492,250
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214479

## Citation

> US National Institutes of Health, RePORTER application 10214479, Role of Tim-1 and Bregs in Tolerance and Autoimmunity (5P01AI129880-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10214479. Licensed CC0.

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