L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

摘要

class="head no_bottom_margin" id="sec1title">IntroductionUpon antigenic stimulation, antigen-specific naive T cells proliferate extensively and acquire different types of effector functions. To support cell growth and proliferation, activated T cells adapt their metabolism to ensure the generation of sufficient biomass and energy (). Unlike quiescent T cells, which require little nutrients and mostly use oxidative phosphorylation (OXPHOS) for their energy supply, activated T cells consume large amounts of glucose, amino acids, and fatty acids and adjust their metabolic pathways toward increased glycolytic and glutaminolytic activity (, , , ).At the end of the immune response, most T cells undergo apoptosis, while a few survive as memory T cells that confer long-term protection (, ). T cell survival is regulated by extrinsic and intrinsic factors. Prolonged or strong stimulation of the T cell receptor (TCR) of CD4⁺ and CD8⁺ T cells promotes “fitness” by enhancing survival and responsiveness to the homeostatic cytokines IL-7 and IL-15, which in turn sustain expression of anti-apoptotic proteins (, , ). Metabolic activity is also critical to determine T cell fate and memory formation (, , ). For instance, triglyceride synthesis is central in IL-7-mediated survival of memory CD8⁺ T cells (), while increased mitochondrial capacity endows T cells with a bioenergetic advantage for survival and recall responses (). Mitochondrial fatty acid oxidation is required for the generation of memory T cells (href="#bib48" rid="bib48" class=" bibr popnode">Pearce et al., 2009), while the mammalian target of rapamycin (mTOR), a central regulator of cell metabolism, has been shown to control T cell memory formation (href="#bib2" rid="bib2" class=" bibr popnode">Araki et al., 2009).Metabolic fitness and T cell survival are particularly crucial in anti-tumor responses because nutrients are often scarce in the tumor microenvironment leading to T cell dysfunction (href="#bib9" rid="bib9" class=" bibr popnode">Chang et al., 2015, href="#bib22" rid="bib22" class=" bibr popnode">Ho et al., 2015), stress, and apoptosis (href="#bib1" rid="bib1" class=" bibr popnode">Alves et al., 2006, href="#bib37" rid="bib37" class=" bibr popnode">Maciver et al., 2008, href="#bib63" rid="bib63" class=" bibr popnode">Siska and Rathmell, 2015). Depletion of glucose may decrease production of interferon (IFN)-γ (href="#bib8" rid="bib8" class=" bibr popnode">Chang et al., 2013) and modulate the differentiation of regulatory T cells (href="#bib14" rid="bib14" class=" bibr popnode">De Rosa et al., 2015). In addition, degradation of L-arginine by myeloid-derived suppressor cells leads to reduced expression of the CD3ζ chain, resulting in impaired T cell responsiveness (href="#bib6" rid="bib6" class=" bibr popnode">Bronte and Zanovello, 2005, href="#bib54" rid="bib54" class=" bibr popnode">Rodriguez et al., 2007). L-arginine is a versatile amino acid that serves as a building block for protein synthesis and as a precursor for multiple metabolites, including, polyamines, and nitric oxide (NO) that have strong immunomodulatory properties (href="#bib21" rid="bib21" class=" bibr popnode">Grohmann and Bronte, 2010).In this study, we took advantage of recent developments in mass spectrometry (href="#bib4" rid="bib4" class=" bibr popnode">Bensimon et al., 2012, href="#bib40" rid="bib40" class=" bibr popnode">Meissner and Mann, 2014, href="#bib76" rid="bib76" class=" bibr popnode">Zamboni et al., 2015) to obtain dynamic proteome and metabolome profiles of human primary naive T cells following activation and found several changes in metabolic pathways. In particular, we found that L-arginine controls glycolysis and mitochondrial activity and enhances T cell survival by interaction with transcriptional regulators. Moreover, L-arginine enhanced the generation of central memory-like T (Tcm) cells with enhanced anti-tumor activity in a mouse model.