Identifying T cell antigens in sarcoidosis

Abstract

Abstract Sarcoidosis is a multisystem disorder which most commonly affects the lungs and involves the accumulation of CD4+ T cells at the sites of disease. The etiology of the disease is unknown, and the lack of a known antigen has hindered the study of disease pathogenesis. However, there is considerable evidence that CD4+ T cells are involved in the initiation and perpetuation of sarcoidosis. Previous work by our lab and others has demonstrated that particular T cell clones within the bronchoalveolar lavage (BAL) have been preferentially expanded in patients with sarcoidosis. These oligoclonal T cell populations accumulate within the lung and disappear with disease resolution. Furthermore, correlations have been observed between the expansions of CD4+T cells expressing the T cell receptor (TCR) α-chain variable (V) region Vα2.3 and the presence of the HLA-DRB1*0301 (DR3) allele in certain patient populations. Preliminary data suggest that cells within the BAL expressing TCRs utilizing Vα2.3, Vβ5.1, and Vβ5.3 are preferentially expanded before and after ex-vivo stimulation with IL-2. We hypothesize that sarcoidosis-specific CD4+ T cells accumulate and expand in the lungs of sarcoidosis patients in response to a specific antigen. To determine whether these expanded CD4+T cell clones play a pathogenic role in disease progression, as well as to address their antigen specificity, the TCRs of these clones have been characterized, and a combinatorial peptide library has been screened to identify candidate antigens that stimulate these clones. These unbiased data will provide clues to the disease-initiating antigens that drive sarcoidosis in a subset of patients and will lead to an extension of our findings to a larger disease cohort.