Pathological immune responses to metal ions such as beryllium (Be), nickel (Ni), and others are among the most common causes of T cell-mediated hypersensitivities in humans, yet the nature of cation presentation to the T cell receptor (TCR) is unknown. In this regard, chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of Be- specific CD4+ T cells in the lung. CBD remains an important public health concern with more than 1,000,000 US workers having been exposed to beryllium and at risk for disease development. Genetic susceptibility is strongly linked to HLA-DP alleles that contain a glutamic acid at the 69th position of the ?-chain (?Glu69), and the majority of CD4+ T cells recognize Be in an HLA-DP-restricted manner. During the previous funding period, we crystallized HLA-DP2, the most prevalent ?Glu69-containing HLA-DP molecule, and showed that its peptide-binding groove of HLA-DP2 was wider than that of other MHCII molecules, opening a solvent-exposed acidic pocket that included ?Glu69 and could easily accommodate a Be-containing compound. We identified a set of related Be-dependent peptides that bind to HLA-DP2 and stimulate a Be-specific TCRs expressed on CD4+ T cells from the lung of a CBD patient. These peptides possess a negatively-charged aspartic and glutamic acid residues at p4 and p7 of the peptide, which surround the putative Be binding site in the HLA-DP2 molecule and serve a novel peptide function in metal-induced hypersensitivity, that being metal ion capture. Be-loaded HLA-DP2-peptide tetramers of this complex predominantly bind to V?5.1-expressing CD4+ T cells from the lungs of HLA-DP2-expressing CBD patients. However, this ligand only accounts for ~5% of Be-responsive T cells in the lung, suggesting that additional peptides complete the TCR ligand for the majority of Be-responsive T cells and that each Be-dependent ligand may be recognized by a different TCR V?-expressing T cell subset. Thus, we hypothesize that Be-dependent peptides will express a unique core motif of acidic amino acids at p4 and p7 that capture and coordinate Be and that each of these Be-dependent ligands will be recognized by a different set of Be-specific CD4+ T cells. The identification of these unknown Be-dependent peptides is essential in order to translate our basic science findings into a set of biomarkers that can identify disease progression and monitor severity. The first specific aim will identify additional Be-dependent peptides to complete the Be-specific TCR ligand for a set of Be-specific CD4+ T cells. Using HLA-DP2 tetramers of these ligands, we will query whether the Be-specific CD4+ T cells that bind to these reagents comprise public TCR repertoire in the second aim. In the third specific aim, we will determine whether tetramers of these Be-dependent ligands can be used as biomarkers of disease progression and severity in Be-exposed subjects. Together, these studies will strengthen our understanding of how antigens cause granulomatous inflammation and specifically how metals antigens trigger an immune response.
This translational study will utilize blood and lung specimens from human subjects with an occupational lung disorder to further our understanding of the beryllium-induced immune mechanisms that lead to disabling lung dysfunction. In a disease characterized by progressive loss of lung function, identifying potential biomarkers of disease progression and severity will likely advance the welfare of this patient population.
|Fontenot, Andrew P (2018) Immunologic Effects of Beryllium Exposure. Ann Am Thorac Soc 15:S81-S85|
|Mitchell, Angela M; Kaiser, Ylva; Falta, Michael T et al. (2017) Shared ?? TCR Usage in Lungs of Sarcoidosis Patients with Löfgren's Syndrome. J Immunol 199:2279-2290|
|Falta, M T; Tinega, A N; Mack, D G et al. (2016) Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice. Mucosal Immunol 9:218-28|
|McKee, Amy S; Fontenot, Andrew P (2016) Interplay of innate and adaptive immunity in metal-induced hypersensitivity. Curr Opin Immunol 42:25-30|
|Munson, Daniel J; Egelston, Colt A; Chiotti, Kami E et al. (2016) Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR. Proc Natl Acad Sci U S A 113:8272-7|
|Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7|
|McKee, A S; Mack, D G; Crawford, F et al. (2015) MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4? T-cell priming. Mucosal Immunol 8:1237-47|
|Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80|
|Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42|
|Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8|
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