Moreover, accumulation of tyrosine phosphorylated protein species (p-tyr), p-ERK and p-Akt was accelarated and enhanced in NSMKD T cells as was initiation and magnitude of Ca2+-fluxing indicating that NSM depletion facilitated early T cell activation (Fig. responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression. == Klf1 Author Summary == Though the ability of measles virus (MV) to impair T cell activation has long been known, it is mechanistically not well understood. We have shown earlier that MV can contact dependently trigger activation of sphingomyelinases which is known to affect compartmentalization of membrane lipids and proteins. Because these are particularly important in the activity of the immune synapse (IS), we investigated whether MV-induced sphingomyelinase activity would interfere at that level with T cell activation. Our study for the first time revealed that the neutral sphingomyelinase 2 (NSM2) is transiently activated in primary T cells by co-stimulation through CD3 and CD28, and that this does occur to dampen early T cell responses. The virus appears to exploit this inhibitory activity of the enzyme to suppress T cell activation by promoting an enhanced and prolonged NSM2 activation. These findings do not only assign a hitherto novel role of the NSM2 in regulating T cell responses, but also reveal a novel strategy for viral T cell suppression. == Introduction == Plasma membrane ceramides are released in response to activation of sphingomyelinases and condense into large platforms which alter biophysical properties of the cell membrane. In addition to other stimuli, ligation of certain surface molecules, also including death receptor family members and viral attachment receptors, efficiently activates neutral and/or acid sphingomyelinase (NSM or ASM, respectively) followed by ceramide release (reviewed in[1][3]). Ceramide enriched membrane microdomains act to regulate sorting of membrane proteins and their signalosomes, and this affects a variety of biological responses including lateral and vertical receptor segregation as particularly relevant for pathogen uptake, apoptosis, cell motility and proliferation[3][6]. Measles virus (MV) causes profound generalized immunosuppression and interference with T cell viability, expansion and function is one of IM-12 its major hallmarks. A plethora of findings supports the interpretation that MV is acquired and transferred by CD150+ antigen-presenting cells to the secondary lymphatic tissues where it can be transmitted to and deplete CD150+ lymphocytes, especially memory T cells[7][9]. Though being infected to a very limited extent, peripheral blood cells IM-12 of patients, however, are generally refractory to expansion driven by polyclonal and antigen-specific stimulation, implying they had been paralysed by mechanisms independently of direct infection. In line with this hypothesis, exposure of uninfected lymphocytes to UV-inactivated MV or the MV glycoprotein complex (gpc) was sufficient to induce their arrestin vitroandin vivo[10][13]. For this, the gpc interacts with an as yet unknown receptor on the surface of T cells (which is not identical to CD150[14]) to abrogate relay of T cell receptor (TCR) signaling at the level of the phosphatidyl-inositol-phosphate-3-kinase (PI3K) and its downstream effectors, Akt kinase, Vav1, Rac1 and Cdc42[15][17]. Because these are also major regulators of actin cytoskeletal dynamics, MV contact induced physical T cell paralysis is reflected by collapse of actin based protrusions and loss of polarity and motility on fibronectin[15]. Thus, by targeting the PI3K, MV abrogates activation of downstream effectors essentially mediating S-phase progression, but also actin dynamics which is of key importance in organizing the functional architecture of the immune synapse (IS) where T cell signaling is initiated and sustained[19]. In order to interfere with IM-12 TCR signaling, MV has to initiate signaling upon binding to T cells itself. This involved sequential activation of NSM2 (the.