Journal Article

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

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

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adaptive immunity / Alveoli / Animal models / Animals / Antigens / Berylliosis / Berylliosis - genetics / Berylliosis - immunology / Berylliosis - pathology / Beryllium / Beryllium - toxicity / Biomedical research / Bronchus / CCL3 protein / CCL4 protein / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - pathology / Chemokine CCL3 - genetics / Chemokine CCL3 - immunology / Chemokine CCL4 - genetics / Chemokine CCL4 - immunology / Chemokines / Chronic Disease / Epitopes / Female / Gene expression / Histocompatibility antigen HLA / HLA-DP beta-Chains - genetics / HLA-DP beta-Chains - immunology / Humans / Immunity, Innate - drug effects / Immunity, Innate - genetics / Lavage / Ligands / Lipopolysaccharides / Lung - immunology / Lung - pathology / Lung diseases / Lungs / Lymphocytes / Lymphocytes T / Male / Mice / Neoantigens / Peptides / Principal components analysis / T cell receptors