Peripheral and Site‐Specific CD4⁺CD28^null T Cells from Rheumatoid Arthritis Patients Show Distinct Characteristics

Abstract

Proinflammatory CD4+CD28null T cells are frequently found in the circulation of RA patients, but are less common in the rheumatic joint. In the present study we sought to identify functional differences between CD4+CD28null T cells from blood and synovial fluid in comparison to conventional CD28 expressing CD4+ T cells. 44 RA patients, displaying a distinct CD4+CD28null T cell population in blood, were recruited for this study and the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4+CD28null T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4+CD28+ T cells and produced higher levels of both IFN-γ and TNF after TCR crosslinking. CD4+CD28null T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4+CD28null cells from the blood, a significant production was observed in CD4+CD28null T cells from synovial fluid. CD4+CD28null T cells were not only found to differ from conventional CD4+CD28+ T cells in the circulation, but we could also demonstrate that synovial CD4+CD28null T cells showed additional effector functions (IL-17 co-production) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28null population.

Expression patterns of CD28 and CTLA‐4 in early, chronic, and untreated rheumatoid arthritis

“…We found almost 100% of the CD4 + T cells expressing CD28 in RA patients and CS, but no differences were observed among groups. This contrasts the other reported studies an expanded subset of CD4 + T cells characterized by a deficiency of CD28 expression (CD28null) and autoreactive behavior in RA patients; therefore, more studies are needed to clarify these findings.…”

Expression of CD4+CD28nullT lymphocytes in children and adolescents with type 1 diabetes mellitus: Relation to microvascular complications, aortic elastic properties, and carotid intima media thickness

“…Increased frequencies of CD4 + CD28 null cells can be found in the peripheral circulation of various immune and inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease . CD4 + CD28 null T‐cells are expanded in type 2 diabetes and associated with poor glycemic control.…”

“…12 Increased frequencies of CD4 + CD28 null cells can be found in the peripheral circulation of various immune and inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. [13][14][15][16] CD4 + CD28 null T-cells are expanded in type 2 diabetes and associated with poor glycemic control. These cells also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an acute coronary syndrome (ACS).…”

Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents

“…As co‐stimulation is a prerequisite for T cell activation, blockade of the co‐stimulatory signalling pathway may represent a potential therapeutic target. The most studied T cell co‐stimulator is the CD28 molecule, widely expressed by all T cells in the mouse and in normal non‐activated human T cells . CD28 binds to CD80 and CD86, which are constitutively present on antigen‐presenting cells (APCs) .…”