Beryllium-specific CD4⁺ T cells induced by chemokine neoantigens perpetuate inflammation

Authors

Michael T. Falta, University of Colorado Anschutz Medical Campus
Jeremy C. Crawford, St. Jude Children's Research Hospital
Alex N. Tinega, University of Colorado Anschutz Medical Campus
Laurie G. Landry, University of Colorado Anschutz Medical Campus
Frances Crawford, National Jewish Health
Douglas G. Mack, University of Colorado Anschutz Medical Campus
Allison K. Martin, University of Colorado Anschutz Medical Campus
Shaikh M. Atif, University of Colorado Anschutz Medical Campus
Li Li, University of Colorado Anschutz Medical Campus
Radleigh G. Santos, Nova Southeastern University
Maki Nakayama, University of Colorado Anschutz Medical Campus
John W. Kappler, National Jewish Health
Lisa A. Maier, University of Colorado Anschutz Medical Campus
Paul G. Thomas, St. Jude Children's Research Hospital
Clemencia Pinilla, Florida International University
Andrew P. Fontenot, University of Colorado Anschutz Medical Campus

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