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

J Clin Invest. 2021 May 3;131(9):e144864. doi: 10.1172/JCI144864.

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.

Keywords: Adaptive immunity; Pulmonology; T cell receptor; T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens
  • Berylliosis / genetics
  • Berylliosis / immunology*
  • Berylliosis / pathology
  • Beryllium / toxicity*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Chemokine CCL3 / genetics
  • Chemokine CCL3 / immunology*
  • Chemokine CCL4 / genetics
  • Chemokine CCL4 / immunology*
  • Chronic Disease
  • Female
  • HLA-DP beta-Chains / genetics
  • HLA-DP beta-Chains / immunology
  • Humans
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Lung / immunology*
  • Lung / pathology
  • Male
  • Mice

Substances

  • Antigens
  • CCL3 protein, human
  • CCL4 protein, human
  • Chemokine CCL3
  • Chemokine CCL4
  • HLA-DP beta-Chains
  • HLA-DPw2 antigen
  • Beryllium