Reduced expression of decay‐accelerating factor 1 on CD4+ T cells in murine systemic autoimmune disease

Abstract

Objective. Deficiency of decay-accelerating factor 1 (termed Daf1 in mice) has been shown to exacerbate autoimmunity, and recent studies have suggested that this may be explained by Daf1 acting as a regulator of T cell immunity. The aim of this study was to determine whether Daf1 expression on T cells is modulated during development of autoimmunity in mice.Methods. To test this hypothesis, we examined Daf1 levels in NZB, DBA/2, and B10.S mice before and after induction of murine mercury-induced autoimmunity (mHgIA). Daf1 was measured by real-time polymerase chain reaction and flow cytometry, and levels of Daf1 were correlated with markers of lymphocyte activation and cytokine production.Results. Autoimmune-prone NZB mice had low endogenous levels of Daf1 irrespective of the induction of mHgIA. Induction of autoimmunity reduced Daf1 expression in mHgIA-sensitive B10.S mice, particularly on activated/memory (CD44 high ) CD4؉ T cells that accumulate as a result of exposure to mercury. Murine mercury-induced autoimmunity-resistant DBA/2 mice, which fail to accumulate CD44 high T cells, showed no change in Daf1 expression. Modulation of Daf1 expression was found to require CD4؉ T cell costimulation, since B10.S mice deficient in CD28 were unable to down-regulate Daf1 or accumulate activated/memory CD4؉ T cells. In B10.S mice exposed to mercury, the production of interleukin-4 (IL-4), but not that of IL-2 or interferon-␥, in the spleen was associated with CD44 high ,Daf1 low ,CD4؉ T cells. Conclusion. These findings demonstrate that reduction of Daf1 expression is closely associated with CD4؉ T cell activation and the accumulation of CD44 high (activated/memory),CD4؉ T cells in both spontaneous and induced systemic autoimmune disease.

Depletion of complement does not impact initiation of xenobiotic‐induced autoimmune disease

“…As expected from previous studies, 20 while IL-4 production was increased in the spleens of animals treated for 1 week s.c. with HgCl 2 , levels of IL-2 and IFN-c mRNA remained unchanged (Fig. 3), and complement depletion did not affect the cytokine profile observed during the development of mHgIA (Fig.…”

“…20 In the present study we demonstrate that complement depletion does not have any effect on T-cell activation and autoantibody production in mHgIA. We also show that the accumulation of CD44…”

“…20 Here, by using flow cytometry analysis, we show that this accumulation of CD44 high Daf1 low CD4 + T cells is not affected by complement depletion (Fig 4a,b). We have also previously reported that Daf1 expression on CD4 + T cells was down-regulated by mercury treatment.…”

“…2,3 We demonstrated that induction of mHgIA in B10.S mice reduced Daf1 expression, leading to an accumulation of CD44 high /Daf low CD4 + T cells in the spleen of mercuryexposed animals. 20 These CD44 high /Daf low CD4 + T cells produced elevated levels of IL-4, 20 a cytokine associated with active mHgIA. 15,16,40 The importance of the downregulation of Daf1 to the autoimmune response was further demonstrated with DBA/2 and CD28-deficient B10.S mice, which are resistant to mHgIA, 18,41 have no change in Daf1 levels and do not exhibit T-cell activation or accumulation following exposure to mercury.…”

“…15,16,40 The importance of the downregulation of Daf1 to the autoimmune response was further demonstrated with DBA/2 and CD28-deficient B10.S mice, which are resistant to mHgIA, 18,41 have no change in Daf1 levels and do not exhibit T-cell activation or accumulation following exposure to mercury. 20 Most recently, Daf1 deficiency in C57BL/6 mice has been argued to result in age-related autoimmunity, including lymphadenopathy, splenomegaly and anti-chromatin autoantibodies, and dermatitis. 42 These observations support the hypothesis that a decrease or deficiency of Daf1 expression is closely associated with CD4 + T-cell activation and cytokine expression during the development of adaptive immune responses in autoimmunity.…”