CD28null T cells in rheumatoid arthritis and inflammatory myopathies : cellular characterization and clinical relevance

Abstract

Rheumatoid arthritis and idiopathic inflammatory myopathies are rheumatic disorders typically displaying infiltrating T cells in the affected organs. Yet, despite much effort, the contribution and antigen specificity of these T cells in association to disease manifestations has not been clearly delineated. In peripheral blood of patients with rheumatoid arthritis, as well as in other chronic inflammatory disorders characterized by infiltrates of CD4+ T cells, oligoclonally expanded CD4+ T cells lacking the costimulatory molecule CD28 are found with increased frequencies. These cells are often referred to as CD4+CD28null T cells and display a proinflammatory profile with secretion of IFN-γ and TNF, as well as cell-mediated cytotoxicity. Expanded populations of the corresponding subset of CD8+ T cells are found in most individuals and are described as effector memory cells associated with latent virus infections.

The aims of this thesis were to perform functional characterization of CD4+CD28null T cells in the two rheumatic diseases, rheumatoid arthritis and idiopathic inflammatory myopathies, as well as to investigate their presence in the inflamed tissue and correlation to clinical manifestations. In idiopathic inflammatory myopathies also CD8+CD28null T cells were investigated.

In rheumatoid arthritis, we found circulating CD4+CD28null T cells in 30% of patients. Screening for natural killer (NK) cell receptors on these cells revealed that CD4+CD28null T cells express a wide variety of both inhibiting and activating NK receptors. Functionally, a selection of these receptors could synergistically costimulate CD4+CD28null T cells after suboptimal T-cell receptor (TCR) stimulation. Thus, costimulation of CD4+CD28null T cells via NK receptors might permit activation via less specific or lower avidity TCR-MHC interactions.

Despite the increased frequencies of CD4+CD28null T cells in peripheral blood of patients with rheumatoid arthritis, CD4+CD28null T cells were only scarcely found in the synovial membrane and fluid of the inflamed joints. Interestingly in approximately half of the patients that displayed an increased frequency of CD4+CD28null T cells in peripheral blood, the dominant TCR-Vβ subsets from peripheral blood were not present in synovial fluid. This indicates a selected migration of CD4+CD28null T cells to the joint. Still, ex vivo synovial CD4+CD28null T cells were functional and displayed a similar response to stimulation as the corresponding cells from peripheral blood. The frequencies of CD4+CD28null T cells in the circulation or synovial fluid did not correlate with erosive arthritis, neither to seropositivity for anti-citrullinated proteins/peptides antibodies. This is not surprising given the low frequency of these cells in the joint. Instead, there was a strong correlation to seropositivity for cytomegalovirus (CMV). These data indicate that CD4+CD28null T cells are not associated with erosive disease in rheumatoid arthritis, but are potentially involved in CMV-related manifestations elsewhere than the joint.

In contrast to rheumatoid arthritis, CD4+CD28null T cells and CD8+CD28null T cells dominated the muscles infiltrates of patients with idiopathic inflammatory myopathies. The frequency of CD8+ T cells was strongly correlated with disease activity in a subset of patients. Circulating CD28null T cells of both the CD4+ and CD8+ lineages were more common in patients compared to healthy controls. Interestingly, the frequency decreased with increased disease duration. Like in rheumatoid arthritis, the presence of CD28null T cells was associated to CMV infection. These results imply that CD28null T cells are important effector T cells in idiopathic inflammatory myopathies, and that CMV could be involved in the pathogenesis in a subset of patients.

As CD28null T cells are regulated partly by other mechanisms than conventional T cells, display an instant inflammatory response, and might be involved in defense to CMV infection as well as in pathogenic mechanisms of rheumatic diseases a better understanding for these cells are important for future therapeutic approaches.