Abstract
IntroductionInterleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. We previously demonstrated reduced levels of circulating IL-7 in rheumatoid arthritis (RA), although high amounts are expressed in joints, suggesting differences between systemic and synovial effects. We observed healthy levels of IL-7 in 48% of RA patients in clinical remission (CR) and aimed to investigate the consequences of IL-7 deficiency on T-cell responses.MethodsWe used RA patients with active disease and in CR presenting various levels of IL-7, to investigate its modulatory effects on T cells by analysing responses to phyto-haemagglutinin (PHA), expression of polarization or survival factors, or suppression by regulatory T cells (Tregs).ResultsIL-7 levels were normal (>10 pg/ml) in 48% of RA patients in CR. Amongst 63 CR patients followed up for 18 months, lack of IL-7 recovery was observed in 13 out of 15 (86%) patients experiencing relapse but only 11 out of 48 (23%) of those who did not (P = 0.0002). Binary regressions showed high significance for below normal IL-7 levels for self-reported maternal family history of arthritis (odds ratio (OR): 7.66, P = 0.006) and a trend for smoking (OR: 3.33, P = 0.068) with no further demographic or clinical associations. Serum IL-7 correlated with restored CD4+T-cell response to PHA (rho = 0.879); this was not related to an increase in T-cell proliferation capacity or expression of survival factors B-cell lymphoma 2 (BCL2) and BCL2-associated protein X (BAX). Expression of Th1 polarization factor (TBET) was also dependent on exposure to IL-7 in vivo (rho = 0.600). In contrast CD25highTregs’ response to PHA was not affected by in vivo IL-7, but their suppression capabilities were related to circulating IL-7 (rho = 0.589). Co-stimulation with IL-7 (mimicking the joint environment) increased responsiveness of CD4+T-cells to PHA, lowering the ability of CD25highTregs to suppress them.ConclusionsOur data demonstrate that IL-7 has a critical role in modulating T-cell function in vivo, possibly explaining opposing effects observed systemically and in the joint. Lack of IL-7 recovery in CR by maintaining a suppressed immune system may be a determinant factor in the occurrence of relapse.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0511-3) contains supplementary material, which is available to authorized users.
Highlights
Interleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity
Serum IL-7 levels are reduced in rheumatoid arthritis (RA) independently of systemic levels of inflammation measured by C-reactive protein (CRP) as previously demonstrated [10]
Ethical limitation prevented access to synovial T cells and collection of synovial fluid (SF) in clinical remission (CR), we have shown that IL7 expression was reduced in synovial tissue biopsies in relation to local inflammation these patients were not in CR (Additional file 1)
Summary
Interleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. Our work on T cells in RA over several years has suggested that particular subsets are lost in RA notably recent thymic emigrants [9,10] naïve and memory CD4+T cells, [9] regulatory T cells (Tregs) [11], and compensated by the presence of abnormal subsets (inflammation related cells, IRCs) [9]. Some of these abnormalities have been shown to be associated with relapse following disease-. IL-7 coordinates ectopic lymphoid formation [23,24,25] as well as T-cell-driven osteoclastogenesis [26,27]
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