Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4+ Conventional versus Foxp3+ Regulatory T Cells

Abstract

CD4 Foxp3 regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4 T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1; Asm) mice, as compared with wt mice, the frequency of Tregs among CD4 T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8 T cells in brains of Asm mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4 T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders.

Immunoregulatory role of acid sphingomyelinase in allergic asthma

“…Further, we found that ASM –/– mice have decreased serum IgE levels and increased proportions of foreign antigen‐induced Treg cells in the lung . Consistent with this concept, we observed that airway tolerance reduced ASM activity in the airways and IgE in serum …”

“…These Treg cells have been described to have a protective role in asthma . These findings further indicate an immunosuppressive phenotype in the absence of ASM and are in line with a recent discovery of Hollmann et al ., describing enhanced Treg cell numbers with a higher suppressive capacity in ASM‐deficient mice …”

Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes – Type 1 Diabetes Prediction and Prevention Study (DIPP)

“…Emerging evidence suggests that dysregulated sphingomyelinase activity in conjunction with cellular apoptosis can result in chronic inflammatory disorder 28 . Furthermore, deficiency for the acid sphingomyelinase has been demonstrated to enhance the proliferation of immunosuppressive T regulatory cells and inhibition of brain cell death in mice 29 . Intriguingly, disruption of sphingolipid metabolism has also been increasingly associated with the development and progression of other metabolic conditions, including obesity and type 2 diabetes 30 .…”

Regulation of Arthritis Severity by the Acid Sphingomyelinase

“…Previously, Asm-deficiency or Asm-inhibition has been linked to increased T reg frequencies in naïve mice [43, 44]. Here, we studied immunized mice and did not detect any differences in T reg cell number in lymph nodes of immunized Smpd1 -/- mice compared to immunized wild-type littermates (Fig.…”

“…Our study also included the analysis of regulatory T cells, whose frequency was not altered in Asm-deficient mice after immunization. Hollmann et al and Zhou et al have previously reported an increase of regulatory T cells upon Asm-deficiency in untreated mice [43, 44]. Zhou et al identified ASM as a negative regulator of T reg development, but also noted opposing effects based on the composition of the cytokine cocktail used for experimental T reg induction in their own and in another study by Kue et al [44, 49].…”