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; National Jewish Health
Radleigh Santos, Nova Southeastern UniversityFollow
Maki Nakayama, University of Colorado Anschutz Medical Campus
John W. Kappler, National Jewish Health; University of Colorado Anschutz Medical Campus
Lisa A. Maier, University of Colorado Anschutz Medical Campus; National Jewish Health
Paul G. Thomas, St. Jude Children’s Research Hospital
Clemencia Pinilla, Florida International University
Andrew Fontenot, University of Colorado Anschutz Medical Campus

Document Type

Article

Publication Date

2-25-2021

Publication Title

The Journal of Clinical Investigation

ISSN

1558-8238

First Page

1

Last Page

65

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 (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.

Comments

The authors thank the Flow Cytometry Shared Resource and the Genomics and Microarray Shared Resource at the University of Colorado Cancer Center. The authors also thank the Santiago lab for use of their PCR machines and Todd Egan for assistance with bioinformatic processing of single cell sequencing data. This work was supported by National Institutes of Health grants (HL62410, HL152756, HL102245, and ES025534) to A.P.F

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

NSUWorks 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; 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.
https://nsuworks.nova.edu/math_facarticles/307

DOI

10.1172/JCI144864