Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.

After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages.

The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8 T cells.

Cyclosporin A is a well-established immunosuppressive drug used to treat or prevent graft-versus-host disease, the rejection of organ transplants, autoimmune disorders, and leukemia. It exerts its immunosuppressive effects by inhibiting calcineurin-mediated dephosphorylation of the nuclear factor of activated T cells (NFAT), thus preventing its nuclear entry and suppressing T cell activation. Here we report an unexpected immunostimulatory effect of cyclosporin A in activating the mammalian target of rapamycin complex 1 (mTORC1), a crucial metabolic hub required for T cell activation.

Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.

CD4 regulatory T (T) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 T cell expression of GOT1, a central enzyme in the malate shuttle.

Regulatory T cell-derived interleukin-15 promotes the diversity of immunological memory.

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1 IL-7Rα CD62L terminal effector memory CD8 T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8 T cell pool.

Rgs16 promotes antitumor CD8 T cell exhaustion.

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (T) cell differentiation are known, comparatively little is known about the regulators of T cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T cell survival in tumors.

CD8 agonism functionally activates memory T cells and enhances antitumor immunity.

Memory CD8 T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8 T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody-mediated activation of memory CD8 T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell-mediated cytotoxicity and promoted effector cytokine production in a glucose- and glutamine-dependent manner.

Skeletal muscle antagonizes antiviral CD8 T cell exhaustion.

CD8 T cells become functionally impaired or "exhausted" in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)-15 production during LCMV clone 13 chronic infection.