Evidence for oligoclonality of T cell receptor δ chain transcripts expressed in rheumatoid arthritis patients

Abstract

The inflamed synovium of rheumatoid arthritis (RA) patients contains gamma/delta T cells which express predominantly T cell receptor (TcR) variable (V) delta 1 and V delta 2 chains. Such T cells may contribute to the pathogenesis of RA. To assess the extent of clonality among these T cell populations we sequenced the junctional regions of rearranged TcR V delta 1-C delta and V delta 2-C delta chain cDNA, after using the polymerase chain reaction (PCR) to amplify TcR delta chain transcripts isolated from synovial membrane mononuclear cells (SMC) of five RA patients. The sequences of these delta chain transcripts were compared with those found in peripheral blood mononuclear cells (PBMC) of the same patients and in PBMC of four healthy controls. In contrast to control PBMC, V delta 1 chain cDNA derived from PBMC of three patients showed a strong bias towards usage of the same V-joining (J) combination and junctional region sequences, although the specific sequences were unique in each patient. However, oligoclonality of the V delta 1 chain was less marked in SMC of two of these patients and absent in SMC of the other patients. For V delta 2, oligoclonality was detected in PBMC of two patients. In SMC of a single patient, a dominant V delta 2 transcript was detected that utilized the J delta 2 segment, which was rarely expressed in the normal TcR repertoire. These results indicate in vivo clonal expansion of V delta 1- and V delta 2-expressing gamma/delta T cells in the peripheral blood of RA patients and a synovial T cell infiltrate which consists largely of polyclonally expanded gamma/delta T cells, but shows clonal dominance in some patients. Our data strongly support a role for V delta 1+ and V delta 2+ gamma/delta T cells in the pathogenesis of RA, and, although the nature of the antigen(s) recognized by these cells remains elusive, this report suggests the potential involvement of antigen(s) specific for the V region and V-J junction.

Peripheral selection of V delta 1+ cells with restricted T cell receptor delta gene junctional repertoire in the peripheral blood of healthy donors.

“…Two studies showed an unrestricted repertoire in PBL from patients and normal controls, but predominant sequences in acute multiple sclerosis (29) and leprosy lesions (28), respectively, suggesting in situ selection of particular VIS1 + cells by so far undefined antigens. One further study demonstrated a restricted V/~I repertoire in the peripheral blood of certain patients with rheumatoid arthritis but not in four healthy controls (30). However, it is worth noting that a recent report of preferential Vis1-J81 junctional repertoires in sarcoidosis, demonstrated a repetitive sequence in cDNA from the PBL of one of the normal control (31).…”

“…In the present work, we have shown that V81-J81junctions, while displaying the extensive alterations of germline sequences that are characteristic of post fetal stages (14), are not randomly represented among PBL V/$1 + cells in a large fraction of healthy donors. The description of such repeated sequences in the PBL of healthy donors is unprecedented since only a few V81-J81 sequences have been published to date (28)(29)(30)(31). Two studies showed an unrestricted repertoire in PBL from patients and normal controls, but predominant sequences in acute multiple sclerosis (29) and leprosy lesions (28), respectively, suggesting in situ selection of particular VIS1 + cells by so far undefined antigens.…”

Chronic Sclerosing Sialadenitis of the Submandibular Gland is Mainly Due to a T Lymphocyte Immune Reaction

“…Observations in experimental allergic encephalomyelitis in mice suggest that the lymphocytes in damaged tissue express only a limited number of variable T-cell receptor gene regions and react with a single or a few epitopes, as observed in organspecific autoimmune diseases (21)(22)(23). In autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, a pronounced clonal expansion of ␥␦ T lymphocytes has been observed (17,18). In our series, a monoclonal/oligoclonal reaction of TCR␥ was observed in 14 of 22 (63.6%) cases, and similar IGH rearrangement patterns were seen in 5 of 22 (22.7%) cases.…”

“…It also seems that the invasion of the epithelium by cytotoxic T cells is independent of the immune reactions in and around the lymphoid follicles. The presence of cytotoxic T cells within damaged tissue is indicative of an autoimmune disease (17,18) but has also been seen in viral diseases, such as CMV and Epstein-Barr virus infection. In the meantime, several animal models have provided new evidence of such autodestructive processes (19,20).…”

Molecular characterization of the Vγ9 T cell receptor repertoire expressed in patients with rheumatoid arthritis

“…The aim of the present study was to assess the clonality of Vy9-bearing T cells in synovial membrane mononuclear cells (SMC) and PBMC of five RA patients, for whomV-J 6 clonality had already been determined [24]. This was achieved by sequencing the V-J junctional regions of Vy9 cDNA, following amplification by the polymerase chain reaction (PCR).…”