Tissue-infiltrating alloreactive T cells require Id3 to deflect PD-1–mediated immune suppression during GVHD

Researchers have discovered a significant function of the Id3 protein in the persistence and operational capabilities of tissue-infiltrating alloreactive T cells, offering insights that could impact the treatment of graft-versus-host disease (GVHD) and the effectiveness of CAR T-cell therapy. The study illustrates Id3's critical role in this context by showing that its absence leads to increased PD-1 expression and compromised functionality of infiltrating Th1 cells. This points towards the potential of targeting Id3 to both alleviate GVHD symptoms and maintain anti-tumor activity, given its influence on the development of T-cell subsets and the modulation of transcription factors driving T-cell dysfunction.

The investigation into Id3's involvement in GVHD brought to light several key findings: naïve CD4+ T cells devoid of Id3 were incapable of inducing GVHD in mouse models, significantly improving recipient survival rates. This was attributed not to an impairment in T-cell proliferation but to a decrease in the population of IFN-γ-producing T cells within GVHD target tissues, especially the liver and intestines. Additionally, Id3 was shown to repress genes linked with effector differentiation and the expression of inhibitory receptors like PD-1 and PD-L1. The blockade of the PD-1 pathway in Id3-deficient T cells interestingly restored their GVHD-inducing abilities, underscoring the pathway's crucial role in T-cell regulation in Id3's absence. These findings highlight Id3's importance in sustaining specific T-cell populations within tissues and offer insights into potential GVHD and CAR T-cell therapy enhancements by modulating Id3-related pathways.

This study also elaborates on how targeting Id3 in T cells might offer a novel approach to mitigate GVHD while preserving the anti-tumor efficacy of treatments like CAR T-cell therapy. The knockout of ID3 in human T cells demonstrated a reduction in the severity of xenogeneic GVHD progression without dampening antitumor activity. Additionally, the study unveiled Id3's function in regulating gene programs that counteract PD-1-mediated T-cell suppression and support CD28 signaling, which is pivotal for T-cell activation and survival. Through scRNA-seq and ATAC-seq analyses, the researchers unveiled Id3's influence on chromatin accessibility and transcription factor engagement at critical gene loci, affecting effector differentiation and PD-1 expression. These comprehensive insights not only highlight Id3's fundamental role in the dynamics of tissue-infiltrating alloreactive T cells but also mark a significant advancement in understanding and potentially treating GVHD and optimizing CAR T-cell therapy.

Reference:

Wang Y, He S, Calendo G, et al. Tissue-infiltrating alloreactive T cells require Id3 to deflect PD-1-mediated immune suppression during GVHD. Blood. 2024;143(2):166-177. https://doi.org/10.1182/blood.2023021126