To clarify the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated Sjögren’s syndrome (SS), the TCR Vβ gene usage by the infiltrating lymphocytes in the target organ was examined. The Vβ families predominantly used in the labial salivary gland (LSG) from the HTLV-I-seropositive (HTLV-I+) SS patients were more restricted than those from the HTLV-I-seronegative (idiopathic) SS patients, and were commonly Vβ5.2, Vβ6, and Vβ7. The single-strand conformation polymorphism analysis revealed that T cell clonotypes with Vβ5.2, Vβ6, and Vβ7 accumulate in the LSG from the HTLV-I+ and idiopathic SS patients. Among junctional sequences of the most dominant Vβ7 transcripts, the conserved amino acid motif (QDXG: X is any amino acid) was found in six of the five HTLV-I+ SS patients and was also detected in two of the five idiopathic SS patients. Using the probes specific to the motif, the Vβ7 transcripts with the motif were detected in the LSG from all of the seven HTLV-I+ and five of the six idiopathic SS patients, but not from eight healthy subjects. The Vβ7 transcripts with this motif were also detected in the HTLV-I-infected T cell lines obtained from the LSG of an HTLV-I+ SS patient. The accumulation of HTLV-I-infected T cells expressing TCR with the conserved motif was thus indicated. These T cells were commonly present in patients with idiopathic SS and are strongly suggested to most likely be involved in the pathogenesis of both HTLV-I-associated and idiopathic SS. 1 This work was supported in part by grants from the Ministry of Education, Science, and Culture of Japan. Abbreviations used in this paper: HTLV-I, human T lymphotropic virus type-I; SS, Sjögren’s syndrome; LSG, labial salivary gland; PG, parotid gland; SSCP, single-strand conformation polymorphism; HAM/TSP, HTLV-I-associated myelopathy/tropical spastic paraparesis; HAAP, HTLV-I-associated arthropathy; CDR3, complementarity-determining region 3.
These results suggest that unique T-cell populations bearing V beta 2, V beta 6, or V beta 19 gene products tend to expand in OLP lesions as a consequence of in situ stimulation with a restricted epitope of either a nominal antigen on the MHC molecule for the majority of the V beta families, even if only in minor populations, or of a common superantigen for the minority of the V beta families.
We recently described that the SART-1 690 -698 peptide could induce HLA-A24-restricted cytotoxic T lymphocytes (CTLs), which recognize the SART-1 259 ؉ tumor cells from peripheral blood mononuclear cells (PBMCs) of HLA-A24 ؉ cancer patients. In our study, in 5 of 14 HLA-A24 ؉ patients with oral squamous cell carcinomas (SCCs), CTLs could be induced with the SART-1 690 -698 peptide from the PBMCs. In 2 of the patients from whom the highest CTL activities were induced, the T-cell receptor (TCR) V repertoire expressed by the SART-1 690 -698 -specific CTLs was found to be restricted and multiple V families were predominantly expressed in each patient. Although the predominant V families were different between the 2 patients, V7 was highly and commonly predominant. The same predominant V families were also detected in the tumor-infiltrating lymphocytes (TILs) from each patient, and each V family contained one or more unique T-cell clonotypes. The unique T-cell clonotypes were found to be common between the TILs and SART-1 690 -698 -specific CTLs from each patient, and especially 2 T-cell clonotypes with V7 were identical even in the 2 patients. Key words: cytotoxic T lymphocytes; HLA-A24; squamous cell carcinoma; T-cell receptor; tumor antigenMany antigenic peptides recognized by HLA class I-restricted cytotoxic T lymphocytes (CTLs) against melanomas have been identified in the past 10 years. 1-5 Some of them are presently being investigated in clinical trial as cancer vaccines and have led to major tumor regression in some patients with melanomas. 6 -8 These tumor-rejection peptides are thus expected to be a new tool for specific immunotherapy to melanomas. In squamous cell carcinomas (SCCs), one of the major cancers in humans, tumorinfiltrating lymphocytes (TILs) are quite commonly observed 9 and specific immunotherapy with the tumor-rejection antigens is thus also expected as a new treatment modality for patients with SCCs. 10 We recently identified a SART-1 gene encoding both the 43 kD of SART-1 259 antigen and the 125 kD of SART-1 800 antigen. 11,12 The SART-1 259 antigen is preferentially expressed in the cytosol of a majority of SCCs and some adenocarcinomas, but not in other types of cancers or any normal cells except for those of the testis, while the SART-1 800 antigen is expressed in the nucleus of all proliferating cells. Therefore, the SART-1 259 antigen is expected to be a source of tumor-rejection peptides recognized by T cells, while the SART-1 800 antigen is not. More recently, we also identified several nonapeptides from the SART-1 259 antigen that are capable of inducing HLA-A26-or A24-restricted and tumor-specific CTLs from peripheral blood mononuclear cells (PBMCs) of patients with esophageal, lung, breast, brain, gynecologic and renal cancers, 12-17 and some of the nonapeptides have already been used in clinical trials for specific immunotherapy of HLA-A26 ϩ or -A24 ϩ patients with SCCs and adenocarcinomas as a cancer vaccine. 18 These antigenic peptides complexed with HLA molecules ...
SUMMARYT-cell receptor ( TCR) ab+ CD4− CD8− (double-negative; DN ) T cells appear in the peritoneal cavity at an early stage of intraperitoneal (i.p.) infection with the intracellular pathogen Listeria monocytogenes. In the present report, we analysed the developmental pathway and functions of the TCRab+ DN T cells using the L. monocytogenes infection system. The TCRab+ DN T cells appeared in the peritoneal cavity after L. monocytogenes i.p. infection in adult-thymectomized lethally irradiated bone marrow chimeras and p56lck-deficient mice. The results demonstrated that the TCRab+ DN T cells can develop extrathymically in a p56lck-independent manner. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the TCRab+ DN T cells expressed genes for interferon-c ( IFN-c), the macrophage chemotactic factors MCP-1 and Eta-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF ) but lacked expression of genes for interleukin-2 ( IL-2), IL-4 and IL-10. As expected from the RT-PCR analysis, the TCRab+ DN T cells produced IFN-c in response to anti-TCRb monoclonal antibody (mAb), anti-CD3 mAb and L. monocytogenes-infected macrophages but IL-4 was undetectable after the stimulation. Furthermore, the intracellular cytokine staining analysis demonstrated that approximately half of the TCRab+ DN T cells detectable at the early stage of L. monocytogenes infection were IFN-c-producing cells. All of the results suggest that the TCRab+ DN T cells develop through a unique extrathymic p56lck-independent pathway and participate in early protection against bacterial infection through activation and accumulation of macrophages.
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