Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice

M. T. Falta, A. N. Tinega, D. G. Mack, N. A. Bowerman, F. Crawford, J. W. Kappler, C. Pinilla, A. P. Fontenot

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4+ T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (βGlu69), and HLA-DPB1∗02:01 is the most prevalent βGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4+ T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vβ6, and a subset of these hybridomas expressed identical or nearly identical β-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4+ T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be 2+ cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.

Original languageEnglish (US)
Pages (from-to)218-228
Number of pages11
JournalMucosal Immunology
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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