Date of this Version
5-1-2021
Document Type
Article
Abstract
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-specific (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 ligand 4 (CCL4) and CCL3. HLADP2–CCL/Be tetramer staining confirmed that these chemokine-derived peptides represented major antigenic targets in CBD. Furthermore, Be induced CCL3 and CCL4 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 cycle of innate and adaptive immune activation.
DOI
10.1172/JCI144864
Recommended Citation
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 G.; Nakayama, Maki; Kappler, John W.; Maier, Lisa A.; Thomas, Paul G.; Pinilla, Clemencia; and Fontenot, Andrew P., "Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation" (2021). All Faculty. 393.
https://digitalcommons.fiu.edu/all_faculty/393