The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo

Abstract

Decay-accelerating factor ([DAF] CD55) is a glycosylphosphatidylinositol-anchored membrane inhibitor of complement with broad clinical relevance. Here, we establish an additional and unexpected role for DAF in the suppression of adaptive immune responses in vivo. In both C57BL/6 and BALB/c mice, deficiency of the Daf1 gene, which encodes the murine homologue of human DAF, significantly enhanced T cell responses to active immunization. This phenotype was characterized by hypersecretion of interferon (IFN)-γ and interleukin (IL)-2, as well as down-regulation of the inhibitory cytokine IL-10 during antigen restimulation of lymphocytes in vitro. Compared with wild-type mice, Daf1−/− mice also displayed markedly exacerbated disease progression and pathology in a T cell–dependent experimental autoimmune encephalomyelitis (EAE) model. However, disabling the complement system in Daf1−/− mice normalized T cell secretion of IFN-γ and IL-2 and attenuated disease severity in the EAE model. These findings establish a critical link between complement and T cell immunity and have implications for the role of DAF and complement in organ transplantation, tumor evasion, and vaccine development.

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

“…37,38 Furthermore, the augmented T-cell responsiveness to activation stimuli in Daf1 knockout mice studies persisted for weeks. 38 A recent study in EAMG suggests that inhibiting complement at the C5 activation step, a DAF target, may also influence the humoral response with altered antibody profiles.…”

Costimulation via CD55 on Human CD4+ T Cells Mediated by CD97

“…The stimulation of cells with anti-CD55 Abs may be a result of direct signaling through CD55 (16 -18) or it may be related to their ability to block CD55-mediated complement inhibition (19,20). Recent studies have shown an enhanced T cell responsiveness in CD55 Ϫ/Ϫ mice.…”

“…Besides direct stimulation, binding of mAbs to CD55 might inhibit CD55 mediated complement regulation, which has been implicated in enhanced T cell responses (19,20). To investigate the effect of anti-CD55 mAbs on complement regulation in our setting, we conducted a series of experiments to assess whether a correlation existed between costimulation with anti-CD55 mAbs and their effect on CD55 complement inhibition.…”

“…Furthermore, cross-linking of CD55 with Abs was shown to result in signal transduction in lymphoid and nonlymphoid cells (16 -18). More recently, two studies on CD55-deficient mice have shown enhanced T cell responses, suggesting that CD55 can directly suppress T cell function (19,20). However, the T cell hyperresponsiveness was shown to be related to enhanced complement activation, due to lack of CD55 complement regulation, because normal responses were restored in CD55 Ϫ/Ϫ C3 Ϫ/Ϫ or CD55 Ϫ/Ϫ Factor D Ϫ/Ϫ double-knockout mice.…”

Effect of complement and its regulation on myasthenia gravis pathogenesis

“…crry-knockout mice die in utero and, therefore, its role in mature animals has not been defined as well as the other regulators. There is emerging evidence that DAF and CD59 suppress T-cell activity where the absence of DAF or CD59 in mice was found to increase T-cell activation [24][25][26].…”