Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII CAR-T cell-treated mice

Area of Science:

• Immunology
• Pulmonary Medicine
• Toxicology

Background:

• Chronic beryllium disease (CBD) involves inflammation and specific T cell responses.
• Elevated CCL3 and CCL4 chemokines correlate with beryllium-specific CD4+ T cells in CBD lungs.

Purpose of the Study:

• To investigate the role of chemokines CCL3 and CCL4 in CBD pathogenesis.
• To evaluate the therapeutic potential of targeting these chemokines or specific T cells.

Main Methods:

• Generated HLA-DP2 transgenic CCL3-deficient mice lacking CCL4.
• Analyzed T cell populations, cytokine production, and cellular aggregates upon beryllium exposure.
• Utilized RNA sequencing to profile CD4+ T cells and tested TNF-α deficiency and CAR-T cell therapy.

Main Results:

• CCL3/CCL4 deficiency attenuated T cell responses and inflammation in mice.
• Dendritic cells were identified as key regulators of chemokine-specific T cell responses.
• RNA sequencing revealed inflammatory and cholesterol metabolism pathways in CD4+ T cells.
• Targeting TNF-α or using CAR-T cells reduced T cell responses and aggregates.

Conclusions:

• CCL3 and CCL4 are crucial for promoting beryllium-specific CD4+ T cell responses in CBD.
• Peptide-MHCII CAR-T cells represent a promising strategy for depleting pathogenic T cells in CBD.