Identification of T cell epitopes in sarcoidosis

Abstract

Sarcoidosis is an inflammatory granulomatous disease that primarily affects the lung. It has a worldwide distribution and affects individuals of all ages. Despite the prevalence of the disease, the cause of sarcoidosis remains unknown. Evidence suggests that CD4+ T cells in the bronchoalveolar lavage (BAL) of sarcoidosis patients are instrumental in disease progression. Löfgren’s syndrome (LS) is an acute form of sarcoidosis with a specific set of inflammatory symptoms. In patients with LS, disease susceptibility has been associated with expression of HLA-DR3 and an expansion of BAL CD4+ T cells expressing T cell receptor (TCR) α-chain variable region (TRAV) 12-1 and TCR β-chain variable region (TRBV) 2. These oligoclonal T cell populations accumulate within the lung and disappear with disease resolution. We hypothesize that in these HLA-DR3+ LS patients, TRAV12-1/TRBV2 CD4+ T cell clones accumulate and expand in the lung in response to unknown etiologic antigens. We have identified a set of expanded and related TRAV12-1/TRBV2 αβTCRs derived from the BAL CD4+ T cells of DR3+ LS patients. We screened T cell hybridomas expressing these disease-relevant TCRs with decapeptide positional scanning libraries and identified stimulatory mimotopes for this set of TCRs. We identified several naturally occurring peptides derived from relevant fungal and bacterial species that stimulate the LS TCRs. Validation of these peptides as pathogenic T cell epitopes in LS is currently underway. Peptides that stimulate LS-associated TCRs have not been discovered until now, making this a major novel achievement in the field. Identification of an etiologic antigen in LS will narrow our search of the stimuli driving sarcoidosis in the US.