Tumor Necrosis Factor Receptor Type I Expression of CD4+ T Cells in Rheumatoid Arthritis Enables Them to Follow Tumor Necrosis Factor Gradients Into the Rheumatoid Synovium

Abstract

Objective. The cytokine tumor necrosis factor (TNF) plays a central role in the pathogenesis of rheumatoid arthritis (RA), but its disease-specific effector mechanisms have not been fully elucidated. This study was undertaken to investigate the role of TNF in T cell accumulation and migration in the synovitic joints of RA patients.Methods. Vital tissue sections from rheumatoid synovium were generated using a horizontally oscillating microtome and were coincubated with fluorescencelabeled CD4؉ T cells. Migration was detected by fluorescence and confocal microscopy. Migrating T cells were recovered from the tissue and analyzed for phenotype. Chemotaxis of CD4؉ T cells from RA patients in response to increasing concentrations of TNF was analyzed in Transwell experiments.Results. CD4؉ T cells from RA patients migrated into the tissue sections in significantly higher numbers than T cells from healthy controls. Migrating CD4؉ T cells differed from nonmigrating ones in their increased expression of TNF receptor type I (TNFRI), which was expressed on a fraction of circulating CD4؉ T cells from RA patients, but not from controls. CD4؉ T cells from the peripheral blood of RA patients were also found to migrate along TNF concentration gradients ex vivo. Accordingly, blockade of either TNF or TNFRI nearly abrogated in vitro T cell migration in synovial tissue.Conclusion. Our findings indicate that the interaction of TNF with TNFRI is pivotal for T cell migration in synovial tissue in vitro, and thereby suggest a relevant role of the cytokine for in vivo T cell trafficking to synovitic joints.

Tumor Necrosis Factor Alpha Gene Polymorphism and Association With Its Serum Level in Iranian Population with Rheumatoid Arthritis

“…9 The interaction of TNF-a with TNF-receptor type I is a migratory stimulus for T CD4 + cells in RA subjects. 10 Therefore, this cytokine is necessary for TCD4+ migration in arthritic joints. Elevated serum level of TNF-a has been reported in RA patients.…”

Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity

“…With respect to the relationship between improvement in clinical disease activity and the augmentation of the CMV response, our data suggest that attenuation of inflammation affects the systemic CMV-specific memory T-cell pool. Speculatively, this could arise due to changes in the number, function, or phenotype of CMV-specific memory T cells circulating in the blood [42,43]. Due to the limitations of this discovery-oriented study, future research is needed to clarify the underlying immune mechanisms and implications of our findings.…”

Multifaceted role of TNF-α during the pathogenesis of rheumatoid arthritis

“…However, the additional role of TNF-α in early phase of T cell migration to arthritic microenvironment, especially adhesion and transmigration through endothelium is not clear. Therefore, Rossol et al [6] observed that the interactions of TNF-α and TNFRI are necessary for T-cell migration into synovium using in vitro and ex vivo experiments. "The results of Rossol et al [6] study show that the interaction of TNF-α with receptor type1 (TNFR1) is indeed a migratory stimulus for CD4+ T cells in RA patients which is a TNF-α gradient dependent".…”