Beryllium-Induced Tumor Necrosis Factor- Production by CD4 T Cells Is Mediated by HLA-DP

Beryllium (Be) presentation to CD4 T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4 T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor(TNF) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti–HLA-DP, but not anti–HLA-DR, monoclonal antibody inhibited Be-stimulated TNFexpression in lung CD3 CD4 T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNFmature-mRNA transcripts, and increased TNFprotein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNFmature-mRNA levels with TNFprotein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4 T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.