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

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Abstract

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(17), DQ2 had increased numbers of lung CD4+ T cells using the T cell receptor (TCR) variable region (V) α 2.3 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(17), 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 Vβ usage by flow cytometry using TCR V-specific monoclonal antibodies or by the polymerase chain reaction (PCR) using Vβ- and Cβ-specific primers. Jβ usage was analyzed by Southern blotting of PCR products and subsequent hybridization with radiolabeled Jβ-specific probes.

Results

Evidence of biased Jα gene segment usage by the α-chains of Vα 2.3+ 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 Vα 2.3+ CD4+ lung T cells were found, with one exception, to have a nonrestricted TCR Vβ usage.

Conclusions

The finding of Vα 2.3+ 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.

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Acknowledgments

We thank Dr. Anders Johannisson for FACS sortings and Dr. Vida Hodara for help with Vβ-Jβ analyses. This work was supported by the Swedish Heart-Lung Foundation, the Swedish Cancer Society, and the Karolinska Institute.

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Authors and Affiliations

  1. Microbiology and Tumorbiology Center (MTC), Karolinska Institute, S-171 77, Stockholm, Sweden

    Johan Grunewald & Hans Wigzell

  2. Department of Biochemistry and Biotechnology, The Royal Institute of Technology, Stockholm, Sweden

    Thomas Hultman

  3. Department of Pharmacology, Pharmacia AB, Uppsala, Sweden

    Anders Bucht

  4. Department of Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden

    Anders Bucht

  5. Institution of Medicine, Pulmonary Section, Karolinska Hospital, Stockholm, Sweden

    Anders Eklund

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  1. Johan Grunewald
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Grunewald, J., Hultman, T., Bucht, A. et al. Restricted Usage of T Cell Receptor Vα/Jα Gene Segments with Different Nucleotide but Identical Amino Acid Sequences in HLA-DR3+ Sarcoidosis Patients. Mol Med 1, 287–296 (1995). https://doi.org/10.1007/BF03401553

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