bims-polyam 2020-05-17 papers

J Allergy Clin Immunol. 2020 May 11. pii: S0091-6749(20)30637-0. [Epub ahead of print]

Regulating T cell differentiation through the polyamine spermidine.

Guilhermina M Carriche, Luís Almeida, Philipp Stüve, Lis Velasquez, Ayesha Dhillon-LaBrooy, Urmi Roy, Marc Lindenberg, Till Strowig, Carlos Plaza-Sirvent, Ingo Schmitz, Matthias Lochner, Anna Katharina Simon, Tim Sparwasser.

BACKGROUND: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites, such as polyamines, by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine and spermidine (SPMD) are abundant within the gastrointestinal tract, and might substantially contribute to gut immunity.
OBJECTIVE: We aimed to characterize the polyamine SPMD as a modulator of T cell differentiation and function.
METHODS: Naïve T cells were isolated from wild type (WT) mice or cord blood from healthy donors, and submitted to polarizing cytokines, with and without SPMD treatment, in order to evaluate T cell differentiation in vitro. Moreover, mice were subjected to oral supplementation of SPMD, or its precursors L-arginine, to assess the frequency and total numbers of Tregs in vivo.
RESULTS: SPMD modulates CD4+ T cell differentiation in vitro, preferentially committing naïve T cells to a regulatory phenotype. Upon SPMD treatment, activated T cells lacking the autophagy gene Atg5 fail to upregulate Foxp3 to the same extent as WT cells. These results indicate that SPMD`s polarizing effect requires an intact autophagic machinery. Furthermore, dietary supplementation with SPMD promotes homeostatic differentiation of Tregs within the gut and reduces pathology in a model of T cell transfer colitis.
CONCLUSION: Altogether, our results highlight the beneficial effects of SPMD, or L-arginine, on gut immunity, by promoting Treg development.

Keywords: Gut immunity; Polyamines; Regulatory T cells; Spermidine; Th17

DOI: https://doi.org/10.1016/j.jaci.2020.04.037

Plant Signal Behav. 2020 May 14. 1761080

The unknown soldier in citrus plants: polyamines-based defensive mechanisms against biotic and abiotic stresses and their relationship with other stress-associated metabolites.

Yasser Nehela, Nabil Killiny.

Citrus plants are challenged by a broad diversity of abiotic and biotic stresses, which definitely alter their growth, development, and productivity. In order to survive the various stressful conditions, citrus plants relay on multi-layered adaptive strategies, among which is the accumulation of stress-associated metabolites that play vital and complex roles in citrus defensive responses. These metabolites included amino acids, organic acids, fatty acids, phytohormones, polyamines (PAs), and other secondary metabolites. However, the contribution of PAs pathways in citrus defense responses is poorly understood. In this review article, we will discuss the recent metabolic, genetic, and molecular evidence illustrating the potential roles of PAs in citrus defensive responses against biotic and abiotic stressors. We believe that PAs-based defensive role, against biotic and abiotic stress in citrus, is involving the interaction with other stress-associated metabolites, particularly phytohormones. The knowledge gained so far about PAs-based defensive responses in citrus underpins our need for further genetic manipulation of PAs biosynthetic genes to produce transgenic citrus plants with modulated PAs content that may enhance the tolerance of citrus plants against stressful conditions. In addition, it provides valuable information for the potential use of PAs or their synthetic analogs and their emergence as a promising approach to practical applications in citriculture to enhance stress tolerance in citrus plants.

Keywords: Candidatus Liberibacter asiaticus; Citrus; Xanthomonas citri; Xylella fastidiosa; abiotic stress; biotic stress; polyamines; putrescine; spermidine; spermine

DOI: https://doi.org/10.1080/15592324.2020.1761080

Blood. 2020 May 13. pii: blood.2019003257. [Epub ahead of print]

Cereblon Harnesses Myc-Dependent Bioenergetics and Activity of CD8+ T lymphocytes.

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only known molecular target for this drug class, where drug-induced ubiquitin-dependent degradation of "neo-substrates" such as IKAROS, AIOLOS, and CK1α accounts for their biological activity. Far less clear is whether these Cereblon E3 ligase modulating compounds disrupt the endogenous functions of CRBN. Strikingly, here we report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T-cells augments their central metabolism manifest as elevated bioenergetics, with supraphysiological levels of polyamines secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Importantly, treatment with Celeblon-modulatingcompounds similarly augments central metabolism of human CD8+T-cell. Notably, the metabolic control of CD8+ T-cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn deficient T-cells have augmented antigen-specific cytolytic activity versus melanoma tumor cells ex vivo and in vivo and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of activated CD8+ T-cells and this phenotype can be exploited by treatment with drugs.

DOI: https://doi.org/10.1182/blood.2019003257