The Journal of Clinical Investigation
Discovering dominant epitopes for T cells, particularly CD4+ T cells, in human immune-mediated diseases remains a significant challenge. Here, we used bronchoalveolar lavage (BAL) cells from HLA-DP2-expressing patients with chronic beryllium disease (CBD), a debilitating granulomatous lung disorder characterized by accumulations of beryllium (Be)-specific CD4+ T cells in the lung. We discovered lung resident CD4+ T cells that expressed a disease-specific public CDR3β T cell receptor motif and were specific to Be-modified self-peptides derived from C-C motif ligands 4 (CCL4) and 3 (CCL3). HLA-DP2-CCL/Be tetramer staining confirmed that these chemokine-derived peptides represented major antigenic targets in CBD. Furthermore, Be induced CCL3 and 4 secretion in the lungs of mice and humans. In a murine model of CBD, the addition of LPS to Be oxide exposure enhanced CCL4 and CCL3 secretion in the lung and significantly increased the number and percentage of CD4+ T cells specific for the HLA-DP2-CCL/Be epitope. Thus, we demonstrate a direct link between Be-induced innate production of chemokines and the development of a robust adaptive immune response to those same chemokines presented as Be-modified self-peptides, creating a vicious cycle of innate and adaptive immune activation.
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Falta, Michael T.; Crawford, Jeremy C.; Tinega, Alex N.; Landry, Laurie G.; Crawford, Frances; Mack, Douglas G.; Martin, Allison K.; Atif, Shaikh M.; Li, Li; Santos, Radleigh; Nakayama, Maki; Kappler, John W.; Maier, Lisa A.; Thomas, Paul G.; Pinilla, Clemencia; and Fontenot, Andrew, "Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation" (2021). Mathematics Faculty Articles. 307.