Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation
Michael T. Falta, … , Clemencia Pinilla, Andrew P. Fontenot
Michael T. Falta, … , Clemencia Pinilla, Andrew P. Fontenot
Published February 25, 2021
Citation Information: J Clin Invest. 2021;131(9):e144864. https://doi.org/10.1172/JCI144864.
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Research Article Pulmonology

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

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. HLA-DP2–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.

Authors

Michael T. Falta, Jeremy C. Crawford, Alex N. Tinega, Laurie G. Landry, Frances Crawford, Douglas G. Mack, Allison K. Martin, Shaikh M. Atif, Li Li, Radleigh G. Santos, Maki Nakayama, John W. Kappler, Lisa A. Maier, Paul G. Thomas, Clemencia Pinilla, Andrew P. Fontenot

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Figure 3

Identification of Be-dependent naturally occurring peptides that stimulate T cell hybridomas expressing the LKGGG CDR3β motif.

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Identification of Be-dependent naturally occurring peptides that stimula...
(A) Sequence logos summarizing hybridoma responses to the D5E8 PSL are shown, depicting amino acids fixed at the listed peptide position by hybridoma activity. Only amino acids with greater than 25% of maximal activity for each hybridoma are shown, and the height of each amino acid (single-letter code) corresponds to the activity of the peptide. If no amino acids are displayed, none met the threshold. The color of each letter groups amino acids by their chemical characteristics. (B) Response of 8 hybridomas expressing LKGGG CDR3β TCRs to naturally occurring peptides plus BeSO4 presented by HLA-DP2–transfected fibroblasts. Peptides are ordered by their biometrical analysis ranking and are included on the list only if at least one of the hybridomas demonstrated a positive response (>200 pg/mL IL-2 at 1.0 μg/mL peptide). Intensity of green color highlights peptides inducing the highest IL-2 secretion. The protein source of each peptide is indicated by its UniProt identification number and name. (C) UniProt number and amino acid sequence of related human chemokine peptides derived from CCL4 and CCL3 (biometrical analysis peptides BA001 and BA002, respectively).