Regulating T cell differentiation through the polyamine spermidine

Abstract 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 Naive 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 naive 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.