HLA-DP2-Transgenic (Tg) mice deficient in CCL3 or treated with novel HLA-DP2/CCL-CAR-T cells show reduced accumulation of chemokine specific-CD4+ T cells in BeO-exposed Lungs 4765

Abstract Description Chemokines are important molecules involved in the recruitment and activation of immune cells and the formation of cellular aggregates. However, how these chemokines and chemokines-specific CD4+ T cells contribute to the pathogenesis of chronic beryllium diseases (CBD) is not well defined. RNA sequencing data of sorted CD4+ T cells showed functional heterogeneity in CCL4 tetramer-positive (CD44+Tet+), and naïve (CD44-Tet-) CD4+ T cells. IFNγ and IL-17 expression were significantly increased in CD44+Tet+ cells compared to the CD44-Tet- CD4+ T cells. BeO exposure showed no difference in the innate immune compartment in HLA-DP2 Tg WT and mice deficient in CCL3, but total and antigen-specific CD4+ T cells were significantly reduced in HLA-DP2 Tg CCL3-/- mice. Additionally, ELISpot data showed a significant reduction in IFNγ -producing CD4+ T cells in the lungs of BeO-exposed CCL3-/- mice. Next, using bone marrow chimeric mice, we established the role of hematopoietic and dendritic cells in controlling Be-induced CCL3 and CCL4 responses in the lungs. Further, in HLA-DP mice deficient in TNF-α or mice administered with the novel HLA-DP CAR-T cells targeting CCL-specific CD4+ T cells, we observed a significant reduction in the number of both CCL3 and 4-specific T cells in the lungs of exposed mice. In conclusion, our findings reveal an important role of hematopoietic cell-derived CCL3/4 in the pathogenesis of CBD and provide CAR-T cells as an alternative therapy for controlling CBD. Funding Sources R01HL152756 Topic Categories Translational and Interventional Immunology (TI)