Highlights d CD8 + T cell function and survival is impaired in HSAN-I patients with SPTLC2 mutation d Mouse CD8 + T cells require SPTLC2 to protect against viral infections d SPTLC2-mediated sphingolipid synthesis prevents mTORC1 hyperactivation and cell death d Sphingolipid supplementation restores SPTLC2-deficient CD8 + T cell effector function
T cells become functionally exhausted in tumors, limiting T cell–based immunotherapies. Although several transcription factors regulating the exhausted T (T ex ) cell differentiation are known, comparatively little is known about the regulators of T ex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T ex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16 + CD8 + tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8 + T cell apoptosis and promoted antitumor effector functions of CD8 + T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8 + T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8 + TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16 -deficient CD8 + T cells. RGS16 mRNA expression levels in CD8 + TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL , TCF7 , and IL7R , and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T ex cell survival in tumors and has implications for improving T cell–based immunotherapies.
During infection, inflammation is an important contributor to tissue regeneration and healing, but it may also negatively affect these processes should chronic overstimulation take place. Similar issues arise in chronic inflammatory gastrointestinal diseases such as inflammatory bowel diseases or celiac disease, which show increasing incidences worldwide. For these dispositions, probiotic microorganisms, including lactobacilli, are studied as an adjuvant therapy to counterbalance gut dysbiosis. However, not all who are affected can benefit from the probiotic treatment, as immunosuppressed or hospitalized patients can suffer from bacteremia or sepsis when living microorganisms are administered. A promising alternative is the treatment with bacteria-derived membrane vesicles that confer similar beneficial effects as the progenitor strains themselves. Membrane vesicles from lactobacilli have shown anti-inflammatory therapeutic effects, but it remains unclear whether the stimulation of probiotics induces vesicles that are more efficient. Here, the influence of culture conditions on the anti-inflammatory characteristics of Lactobacillus membrane vesicles was investigated. We reveal that the culture conditions of two Lactobacillus strains, namely, L. casei and L. plantarum, can be optimized to increase the anti-inflammatory effect of their vesicles. Five different cultivation conditions were tested, including pH manipulation, agitation rate, and oxygen supply, and the produced membrane vesicles were characterized physico-chemically regarding size, yield, and zeta potential. We furthermore analyzed the anti-inflammatory effect of the purified vesicles in macrophage inflammation models. Compared to standard cultivation conditions, vesicles obtained from L. casei cultured at pH 6.5 and agitation induced the strongest interleukin-10 release and tumor necrosis factor-α reduction. For L. plantarum, medium adjusted to pH 5 had the most pronounced effect on the anti-inflammatory activity of their vesicles. Our results reveal that the anti-inflammatory effect of probiotic vesicles may be potentiated by expanding different cultivation conditions for lactobacilli. This study creates an important base for the utilization of probiotic membrane vesicles to treat inflammation.
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