Decreased Expression of Signal‐Transducing CD3 ζ Chains in T Cells from the Joints and Peripheral Blood of Rheumatoid Arthritis Patients

Abstract

Although T cells from patients with rheumatoid arthritis (RA) have previously been determined to have poor proliferative responses to a variety of stimuli, the underlying mechanism is not known. We have investigated the expression of the signal-transducing zeta molecule in subsets of T cells and natural killer (NK) cells derived from the peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of RA patients using quantitative flow cytometry, Western blot analysis and immunohistochemistry. A decrease of zeta expression was apparent in all investigated lymphocyte subsets from the PBMC and SFMC of RA patients, as compared to the corresponding subsets from healthy age- and sex-matched controls. A less pronounced reduction of cell surface-located CD3 epsilon, CD4 and CD8 was also located in T cells from SFMC as compared to PBMC from RA patients. Biochemical demonstration of the low or absent CD3 zeta in PBMC from patients with RA was achieved by Western blot analysis. Immunohistochemical staining and image analysis also confirmed the low expression of zeta chains in synovial tissue of RA patients. The possibility that the decreased expression of zeta and of immune functions of T cells from RA patients may be related to the presence of free oxygen radicals, as we have previously reported in cancer patients, should be considered.

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

“…Alteration of p56 lck has also been found in other pathological situations, such as leprosy (57), cancer (58), rheumatoid arthritis (59), and lupus erythematosus (60). In cancer, this reduction was found to be secondary to the development of the tumors, partially reversible in vitro upon normal mitogenic stimulation and correlated with the clinical outcome (61).…”

Displacement of Linker for Activation of T Cells from the Plasma Membrane Due to Redox Balance Alterations Results in Hyporesponsiveness of Synovial Fluid T Lymphocytes in Rheumatoid Arthritis

“…The decreased expression of the TCR -chain is not only observed in the hyporesponsive SF T lymphocytes from RA patients but also in tumor-infiltrating T lymphocytes from human cancer patients and in the hyporesponsive T lymphocytes from HIV-infected individuals. In all cases, only the expression of the TCR -chain is reduced, while the expression of other components of the TCR/CD3 complex remains constant (30,31,(37)(38)(39). Although the correlation between the hyporesponsive state of the T lymphocytes and the reduced TCR expression suggests a causal relationship, formal evidence for this hypothesis is not available.…”

“…First, it has been observed that the expression of the signaling chain of the TCR/CD3 complex, the TCR -chain, is down-regulated in SF T lymphocytes (30,31). Second, the tyrosine phosphorylation of substrates upon TCR stimulation shows an aberrant pattern in SF T lymphocytes.…”

T Cell Rewiring in Differentiation and Disease

“…A reduction in the expression of CD3 chain has been shown to occur in T cells associated with viral infections such as HIV (79), EBV-and CMV-mediated infectious mononucleosis (80), cancer (81)(82)(83), and autoimmune diseases including rheumatoid arthritis (RA) (84) and systemic lupus erythematosus (SLE) (85). Although T cells in RA demonstrate CD3⑀ loss as well (86), tumor-infiltrating lymphocytes (TILs) demonstrate an additional loss of CD3␥ (83). The involvement of chronic immune activation in the mediation of some of these effects is suggested by the effector phenotype of T cells in autoimmune diseases such as RA and SLE (87,88).…”