Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4+ Conventional versus Foxp3+ Regulatory T Cells.
Claudia HollmannSandra WernerElita AvotaDajana ReuterLukasz JaptokBurkhard KleuserErich GulbinsKatrin Anne BeckerJürgen Schneider-SchauliesNiklas BeyersdorfPublished in: Journal of immunology (Baltimore, Md. : 1950) (2016)
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.
Keyphrases
- regulatory t cells
- wild type
- high fat diet induced
- dendritic cells
- cell death
- mouse model
- type diabetes
- gene expression
- oxidative stress
- spinal cord
- signaling pathway
- dna methylation
- adipose tissue
- cell therapy
- metabolic syndrome
- cancer therapy
- blood brain barrier
- immune response
- spinal cord injury
- drug delivery
- endothelial cells
- copy number
- cell cycle arrest