# The novel role of MIF-CD74 inflammatory pathway in immune regulation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $440,383

## Abstract

Inflammation negatively affects Tregs stability and suppressive function, impairs the
induction of solid organ transplant tolerance and enhances acute and chronic rejection, leading
to worse recipients’ long-term outcomes. Insights into key inflammatory pathways that suppress
Tregs during allo-immune activation can revolutionize our therapeutic approach to promoting
stable endogenous Tregs.
 Our work strongly suggests that an inflammatory cytokine, macrophage migration
inhibitory factor (MIF), secreted by myeloid cells and alloreactive T cells during rejection and
inflammation binds CD74 (MIF receptor) on the surface of activated Tregs to dampen its function
and homeostasis with opposite effect on alloreactive T cells. We show that inhibiting this novel
pathway either through monoclonal antibodies or genetic deletion promotes immune regulation
and induce exhaustion of alloreactive T cells leading to indefinite heart allograft survival in a
murine fully mismatched model. MIF is a potent pro-inflammatory cytokine produced and released
by immune cells, particularly macrophages, and plays an integral role in innate immunity.
However, its role in adaptive immunity is not well known and will be investigated. Our data show
that graft infiltrating Tregs and Teff upregulate their expression of MIF receptor CD74. However,
graft infiltrating myeloid cells and Teff but not Tregs secrete MIF. MIF then binds to CD74 on
Tregs surface to suppress and on Teff to promote their function.
 Our single cell transcriptomic analysis, TCR sequencing, flow cytometry and functional
assays showed that CD74 deficient graft infiltrating Tregs reduced Interferon regulatory factor 1
(IRF1) and shifted toward a more stable Treg phenotype that exhibits superior suppressive ability
in vitro and in vivo. IRF1 is a negative regulator of Foxp3 transcriptional activity that contributes
significantly to Treg instability in the setting of inflammation. Interestingly, CD74 signaling is
exerted through its intracellular-domain (ICD), shown to bind to transcription factors to modulate
gene expression. Recent work identified IRF1 as one of the binding TFs for CD74-ICD13.
 In this application we will test the hypothesis that a novel inflammatory pathway in which
MIF produced by myeloid cells and Teff suppresses Treg function through IRF1 mediated CD74
signaling (SA1), while promoting the Teff function (SA2). We will also develop a clinically relevant
strategy to dampen the MIF mediated inflammatory process in the allograft using anti-CD74
monoclonal antibody generated in our lab (SA3). This anti-mouse CD74 is equivalent to the FDA
approved human anti CD74 (milatuzumab). Hence, this work has high translation potentials.

## Key facts

- **NIH application ID:** 10776908
- **Project number:** 1R01AI179986-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jamil Azzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,383
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10776908

## Citation

> US National Institutes of Health, RePORTER application 10776908, The novel role of MIF-CD74 inflammatory pathway in immune regulation (1R01AI179986-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10776908. Licensed CC0.

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