# Role of Tim-3:Bat-3 pathway in inducing tolerogenic DCs and peripheral tolerance

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $434,860

## Abstract

PROJECT SUMMARY
We cloned TIM 3 as a molecule differentially expressed on IFN-g producing T cells and has emerged as a major
inhibitory molecule necessary for the termination of effector T cell responses. Tim 3 expression is increased on
effector T cells in human chronic viral infections and cancers, rendering them dysfunctional. In contrast, in human
autoimmune diseases, there is loss of Tim 3 expression on effector T cells, rendering them highly pro-
inflammatory and pathogenic. Because of its role in T cell exhaustion, Tim 3 is being targeted in multiple clinical
trials for cancer. Tim 3 is also expressed constitutively on dendritic cells (DCs), however, the role and function
of Tim 3 on DCs is not well understood and this is especially important to understand, in the view of clinical trials
that are underway with anti-Tim 3 antibodies.
As in T cells, Tim 3 is co-expressed in DCs with its adapter protein Bat-3, where Bat-3 acts as a molecular “gate-
keeper”, that restricts Tim 3 signaling and function. To understand the function of Tim 3 in DCs, we have
generated conditional “knock-out” mice of both Tim 3 and Bat-3 in DCs. Initial studies indicate that unrestricted
signaling of Tim 3 in the absence of Bat-3, makes Bat-3-deficient DCs tolerogenic such that they do not effectively
induce inflammatory T cell responses and the mice are resistant to development of autoimmunity. Based on our
preliminary data, we hypothesize that unabated Tim 3 signaling in DCs promotes generation of tolerogenic DCs.
To address this hypothesis, we propose two specific aims:
1. Determine how the Tim 3/Bat-3 interaction regulates development of tolerogenic DCs. We have observed
 that unopposed signaling of Tim 3, by deleting Bat-3, specifically in DCs inhibits development of multiple
 autoimmune diseases including Experimental Autoimmune Encephalomyelitis (EAE) which is the focus
 of this proposal. Using conditional “knock-out” mice for both Tim 3 and Bat-3 in DCs, we propose to
 determine whether resistance to autoimmunity in Bat-3 cKO mice is partly or completely restored by
 deletion of Tim 3 from the same set of DCs. Furthermore, this will also allow us to determine how loss of
 Bat-3 regulates DC phenotype and function.
2. Determine the molecular mechanism by which interaction of Tim 3 and the Smad/TGF-b pathway
 promotes the generation of tolerogenic DCs. Using an unbiased proteomic screen to identify molecules
 that bind to the Tim 3 tail in the absence of Bat-3, we identified Smad-2, a transducer of TGF-b pathway,
 as a Tim 3 interacting protein. This novel observation allows us to study the mechanism by which Tim 3
 mediates its inhibitory function, specifically we will be able to determine the molecular basis by which Tim
 3/Smad/TGF-b pathway promotes the development of tolerogenic DCs. Using high density temporal
 transcriptional analysis of the Tim 3 and Bat-3 deficient DCs, we propose to develop transcriptional
 networks by which the Tim 3:Bat-3 pathway m...

## Key facts

- **NIH application ID:** 10333307
- **Project number:** 5R01AI144166-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,860
- **Award type:** 5
- **Project period:** 2020-02-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333307

## Citation

> US National Institutes of Health, RePORTER application 10333307, Role of Tim-3:Bat-3 pathway in inducing tolerogenic DCs and peripheral tolerance (5R01AI144166-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10333307. Licensed CC0.

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