Sphingomyelinase activation in T cells: Implications for T cell activation and paralysis

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T cell paralysis is a major hallmark of measles virus (MV) induced generalized immunosuppression. We found that activation of the neutral, but not the acid sphingomyelinase takes part in physiological T cell co-stimulation in a timely and spatially restricted and coordinated transient manner. This is perturbed upon MV interaction with T cells, which causes prolonged activation of both NSM and ASM, and this appeared causatively linked to MV-induced loss of actin cytoskeletal dynamics in co-stimulated T cells. To identify molecular targets and pathways involved in MV deregulations of T cell activation at the level of sphingolipid dynamics, we first addressed the general role of sphingomyelinases in T cell activation and defined firstly, their importance in basal and stimulated metabolic T cell programming. Thus, pharmacological inhibition of NSM elevated general levels of both OXPHOS and glycolysis, and pharmacological inhibition of basal ASM activity prevented TCR stimulated oxidative phosphorylation (OXPHOS) bursting. Importantly, MV abrogated the TCR-induced OXPHOS burst, and and this was prevented by NSM inhibition. In the second funding period, we will identify cellular targets of NSM or ASM dependent regulation of OXPHOS versus glycolysis in co-stimulated T cells and their potential de-regulation by MV. Secondly, we found that NSM was required for CD3 signaling, and we will now address targets and mechanisms of NSM in CD3 signaling and their modulation by MV at the level of lipid and signalosome composition. The very same strategy will be employed for our third research focus: ASM activation by CD28 ligation alone appeared to prevent access of this co-stimulatory receptor to the TCR signaling machinery. Upon antigen recognition, signals emanating from the TCR licensed CD28 for co-stimulation by abrogating ASM activation. We will decipher mechanisms of TCR-mediated silencing of ASM activation by co-stimulating receptors. By this we aim to establish whether licensing versus silencing at the level of sphingomyelin breakdown and/or ceramide release is a general concept in co-stimulation and co-inhibition with the obvious goal to evaluate consequences if this is qualitatively de-regulated upon MV interaction.