Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

Significance Genetic linkage to major histocompatibility complex class II proteins has been observed in many immunological disorders; yet, little is known about the underlying mechanisms of these associations. For chronic beryllium disease (CBD), the linkage to HLA-DPB1 alleles encoding a glutamic acid at position 69 of the β-chain is well established. We tested whether the presence of HLA-DP2 is sufficient for the development of a disease-specific model of CBD. HLA-DP2 transgenic mice developed a beryllium-specific adaptive immune response composed of CD4+ T cells that secrete Th1-type cytokines and are HLA-DP2-restricted, thus replicating the major features of the human disease. In addition, regulatory T cells modulate granuloma formation in the lungs of beryllium oxide-exposed HLA-DP2 transgenic mice. Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4+ T cells and included regulatory T (Treg) cells. Beryllium-responsive, HLA-DP2–restricted CD4+ T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2–peptide tetramers, we identified Be-specific CD4+ T cells in the mouse lung that recognize identical ligands as CD4+ T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4+ T cells expressed forkhead box P3, consistent with the expansion of antigen-specific Treg cells. Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of Treg cells to modulate the beryllium-induced granulomatous immune response.