Restricted Usage of T Cell Receptor Vα/JαGene Segments with Different Nucleotide but Identical Amino Acid Sequences in HLA-DR3+Sarcoidosis Patients

Background: Sarcoidosis is a granulomatous disease characterized by the accumulation of activated T cells in the lungs. We previously showed that sarcoidosis patients expressing the HLA haplotype DR3(<xref ref-type="bibr">17</xref>), DQ2 had increased numbers of lung CD4⁺T cells using the T cell receptor (TCR) variable region (V) α2.3 gene segment product. In the present study, the composition of both the TCR α- and β-chains of the expanded CD4⁺lung T cells from four DR3(<xref ref-type="bibr">17</xref>), DQ2⁺sarcoidosis patients was examined. Materials and Methods: TCR α-chains were analyzed by cDNA cloning and nucleotide sequencing. TCR β-chains were analyzed for Vβusage by flow cytometry using TCR V-specific monoclonal antibodies or by the polymerase chain reaction (PCR) using Vβ- and Cβ-specific primers. Jβusage was analyzed by Southern blotting of PCR products and subsequent hybridization with radiolabeled Jβ-specific probes. Results: Evidence of biased J_αgene segment usage by the α-chains of Vα2.3⁺CD4⁺lung T cells was found in four out of four patients. Both different α-chain nucleotide sequences coding for identical amino acid sequences and a number of identically repeated α-chain sequences were identified. In contrast, the TCR β-chains of FACS-sorted V_α2.3⁺CD4⁺lung T cells were found, with one exception, to have a nonrestricted TCR V_βusage. Conclusions: The finding of V_α2.3⁺CD4⁺lung T cells with identical TCR α-chain amino acid sequences but with different nucleotide sequences strongly suggests that different T cell clones have been selected to interact with a specific sarcoidosis associated antigen(s). The identification of T cells with restricted TCR usage, which may play an important role in the development of sarcoidosis, and the possibility of selectively manipulating these cells should have important implications for the treatment of the disease.