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

Michael T. Falta,¹ Masoom Raza,¹ Caley J. Nevienski,¹ Tonya M. Brunetti,² Rui Fu,³ Rebecca M. Tucker,¹ Joseph M. Gaballa,¹ Faiz Minhajuddin,¹ Kibrom M. Alula,¹ Alberto Dinarello,¹ Douglas G. Mack,¹ Allison K. Martin,¹ Joseph C. Onyiah,¹ Michael Yarnell,⁴ Prashanth Francis,⁴ Terry J. Fry,⁴ Lisa A. Maier,¹ Andrew P. Fontenot,¹ Charles A. Dinarello,¹ and Shaikh M. Atif¹

Published June 9, 2026 - More info

In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4⁺ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3^-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3^-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4⁺ T cells, IFN-γ-producing CD4⁺ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4⁺ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4⁺ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4⁺ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4⁺ T cell responses and highlight peptide-MHCII CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4⁺ T cells in CBD.

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