# TGF-β regulated Tim-3 sustains macrophage phagocytic function and confers protection in Plasmodium yoelii NSM-infected mice

## TL;DR

A new role for Tim-3 in macrophages during malaria infection is discovered, showing it helps control the infection by boosting phagocytosis and protecting against parasite-induced cell death.

## Contribution

Identification of a novel TGF-β–Tim-3 axis that sustains macrophage phagocytic function and immune homeostasis during malaria.

## Key findings

- Tim-3+ macrophages show enhanced antigen presentation and proinflammatory traits during Plasmodium infection.
- Blocking Tim-3 worsens disease severity and reduces macrophage phagocytosis of infected red blood cells.
- TGF-β regulates Tim-3 expression, and its stimulation enhances macrophage protection against iRBC-induced cell death.

## Abstract

T-cell immunoglobulin and mucin domain 3 (Tim-3) is a critical immune checkpoint, yet its role in regulating macrophage function during malaria infection remains poorly understood.

We established a Plasmodium yoelii NSM murine model, in vitro co-culture systems, and comprehensive techniques including scRNA-seq, flow cytometry, and functional assays to investigate Tim-3 expression on splenic macrophages and its immunoregulatory impact.

We observed a significant infection-induced downregulation of Tim-3 on splenic macrophages. Transcriptomic profiling revealed that Tim-3+ macrophages exhibited enhanced antigen presentation and a proinflammatory phenotype characterized by elevated reactive oxygen species (ROS) and proinflammatory cytokine production. Blockade of Tim-3 in vivo exacerbated disease severity, increased parasitemia, and impaired macrophage phagocytic capacity, without directly affecting T-cell responses. Mechanistically, we identified transforming growth factor-beta (TGF-β) as a key upstream regulator of Tim-3 expression, as TGF-β signaling was suppressed during infection, and its stimulation or inhibition correspondingly upregulated or downregulated Tim-3. Furthermore, TGF-β-induced Tim-3 upregulation potentiated macrophage phagocytosis of infected red blood cells (iRBCs) and conferred protection against iRBC-induced cell death.

Our results reveal a novel protective TGF-β–Tim-3 axis that maintains the phagocytic function of macrophages and immune homeostasis in Plasmodium yoelii NSM infection. These findings highlight Tim-3 on macrophages as a potential therapeutic target for modulating host defense against malaria infection.

The online version contains supplementary material available at 10.1186/s13071-026-07287-3.