The Presumed Hyporesponsive Behavior of Rheumatoid Arthritis T Lymphocytes Can Be Attributed to Spontaneous Ex Vivo Apoptosis rather than Defects in T Cell Receptor Signaling (original) (raw)
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Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis
Immunology Letters, 1997
In rheumatoid arthritis (RA), the functional status of T cells is incompletely understood. Synovial T cells display phenotypic evidence of former activation, but there is poor production of T cell-derived cytokines in the synovium. in addition, synovial T cell proliferation upon mitogenic and antigenic stimulation was decreased compared with that in peripheral blood T cells. Moreover, previous reports revealed that early Ca2+ rises induced by TCR/CD3 stimulation were decreased in RA T cells compared with those in healthy controls. To investigate the molecular mechanisms of RA synovial T cell hyporesponsiveness, we analyzed the TCR/CD3-mediated protein tyrosine phosphorylation in RA peripheral blood and synovial fluid (SF) T cells. SF T cells exhibited a decreased overall tyrosine phosphorylation pattern upon stimulation. Most notably, the induction of phosphorylation of p38 was virtually absent. Moreover, we found that tyrosine phosphorylation of the TCR 5-chain, one of the most proximal events in TCR signaling, is clearly diminished in RA SF T cells. The decrease in tyrosine phosphorylation was accompanied by a decrease in detectable levels of 5-protein within synovial T cells. These results suggest that a defective TCR signaling underlies the hyporesponsiveness of synovial T cells in RA. The /ourna/ of Immunology, 1997, 159: 2973-2978.
Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis
2018
How pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77, a marker of T cell antigen receptor (TCR) signaling, to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. Moreover, the enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyper-responsive to IL-6. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA. Additionally, endogenous Nur...
Arthritis & Rheumatism, 2009
Methods. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA؉ RA patients, 7 ACPA-RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.
Clinical & Experimental Immunology, 2012
T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and backcrossed into arthritis-prone BALB/c background. Although more than 90% of CD4 + T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4 + T cells expressed approximately twice more TCR-Vb4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4 + T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: 'optimal' TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas 'supraoptimal' TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease.
Biochemical and Biophysical Research Communications, 1999
Previously, we demonstrated the presence of at least two distinct subpopulations of patients with rheumatoid arthritis (RA) employing a cell-transfer experiment using severe combined immunodeficient (SCID) mice. One group of patients, whose T cells derived from the rheumatoid joints, induced synovial hyperplasia (SH) in the SCID mice (the positive group). The other group did not display the induction of SH (the negative group). TCR/V gene usage analysis indicated that some dominant T cell subpopulations were oligoclonally expanding only in the rheumatoid joints, and not in the periphery of the patients of the positive group. Moreover, these T cell subpopulations were not seen in the joints of patients in the negative group or in non-RA patients. In addition, the preferential uses of certain TCR/Vs (V8, V12, V13, and V14) genes were demonstrated in these T cells. In this study, to investigate whether these T cells are driven by a certain antigen(s), the third complementarity determining regions (CDR3s) of TCR/V, especially V8 and V14 PCR products, were cloned and sequenced. As a result, a dominant CDR3 sequence, CASS-PRERAT-YEQ, was found in V14؉ T cells from the rheumatoid joint of a patient (Patient 1) of the positive group with a V14 skew. The identical CDR3 sequence also predominated in V14؉ T cells from the rheumatoid joint of another patient (Patient 7) of the positive group with a V14 skew. In addition, in the patients (Patients 4, 7, 8) of the positive group with a V8 skew, other dominant CDR3 sequences, CASS-ENS-YEQ and CASS-LTEP-DTQ, were found as in the case of V14. However, no identical CDR3 sequences were detected dominantly in the joints of the patients in the negative group or in non-RA patients. A V14؉ T cell clone (TCL), named G3, with the identical CDR3 sequence, CASS-PRERAT-YEQ, was isolated successfully from Patient 1, and cell transfer of G3 with autologous irradiated peripheral mononuclear cells induced SH in the SCID mice. Taken together, these results suggest that T cells inducing SH, thought to be pathogenic for RA, might be driven by a certain shared antigen(s).
1994
T lymphocytes reactive with as yet undefined joint-localized foreign or autoantigens may be important in the pathogenesis of RA. Molecular studies demonstrating skewed T cell antigen receptor (TCR) variable gene usage and selective expansion of particular T cell clones within the synovial compartment support this view. Based on our recent study documenting selective expansion of V1317+ T cells in RA, we have pursued the identification of T cells relevant to the disease process, in an informative patient, by combining molecular analysis of freshly explanted RA synovial tissue V(317 TCR transcripts with in vitro expansion of V,B17+ synovial tissue T cell clones. Peripheral blood V/317 cDNA transcripts proved heterogeneous. In contrast, two closely related sequences, not found in the peripheral blood, dominated synovial tissue V,f17 transcripts, suggesting selective localization and oligoclonal expansion at the site of pathology. CD4+, V.817+ synovial tissue-derived T cell clones, isolated and grown in vitro, were found to express TCR 8 chain transcripts homologous to the dominant Vj817 synovial tissue sequences. One clone shares with a dominant synovial tissue sequence a conserved cluster of 4/5 amino acids (IGQ-N) in the highly diverse antigen binding CDR3 region, suggesting that the T cells from which these transcripts derive may recognize the same antigen. These findings have permitted a complete characterization of the cr/ f8 TCR expressed by putatively pathogenic T cell clones in RA. Functional analysis suggests that the conserved CDR3 sequence may confer specificity for, or restriction by, the MHC class II antigen, DR4.
Rheumatology (Oxford, England), 2000
Autoreactive T cells may contribute to the pathogenesis of rheumatoid arthritis (RA). We studied the T-cell receptor (TCR) V-gene repertoire in the blood and synovium of early and chronic RA patients using polymerase chain reaction-enzyme-linked immunosorbent assay to evaluate possible differences between these patient groups. Over-represented TCR V genes were observed in the synovium, but not in the blood of all RA patients (n = 38). The number of over-represented V genes was higher in the synovium of chronic RA patients (n = 31) than in that of early RA patients (n = 7). The V-gene profile was different among patients, and similar in the two knees for patients with bilateral synovitis (n = 5). The clonal composition of over-represented TCR BV genes in a patient with early RA and a patient with chronic RA was further studied by CDR3 region sequence analysis. A high level of clonal diversity was found in the joints and the blood of the early RA patient, suggesting a polyclonal T-cel...