Antigen receptor control of methionine metabolism in T cells

Immune activated T lymphocytes modulate the activity of key metabolic pathways to support the transcriptional reprograming and reshaping of cell proteomes that permits effector T cell differentiation. The present study uses high resolution mass spectrometry and metabolic labelling to explore how murine T cells control the methionine cycle to produce methyl donors for protein and nucleotide methylations. We show that antigen receptor engagement controls flux through the methionine cycle and RNA and histone methylations. We establish that the main rate limiting step for protein synthesis and the methionine cycle is control of methionine transporter expression. Only T cells that respond to antigen to upregulate and sustain methionine transport are supplied with methyl donors that permit the dynamic nucleotide methylations and epigenetic reprogramming that drives T cell differentiation. These data highlight how the regulation of methionine transport licenses use of methionine for multiple fundamental processes that drive T lymphocyte proliferation and differentiation.
eLife digest White blood cells known as T cells are an essential part of the immune system. If these cells do not work properly the immune system falls down, leading to disease and eventually death. T cells have receptors on their surface that can detect molecules that do not belong in the body and that may indicate an infection or cancer. When one of these foreign molecules is detected, the T cell will activate and transform to become better equipped to protect the body. These two processes known as activation and differentiation involve extensive changes within the T cell. Many of these changes rely on the addition of a small chemical tag onto molecules such as DNA, RNA or proteins. The tag, a methyl group, is most often obtained by breaking down a chemical called methionine, one of the building blocks of proteins. Like all other animals, humans cannot make methionine, and so we must instead obtain it through our diet or recycle it from existing proteins. This raised some questions: does the availability of methionine limit the activity of T cells? And, if so, is it the uptake or breakdown of methionine that has the biggest effect? Sinclair et al. answered these questions by studying T cells from mice. First, the T cells were activated, the proteins from those cells were then collected and quantified using a technique called high resolution mass spectrometry. In further experiments, the uptake and use of a radioactively labeled version of methionine was followed in activated T cells. Using these approaches, Sinclair et al. showed T cell activation increased the cells demand for methionine, and that T cells need a steady supply of methionine to remain activated. The main limiting factor in this process was the speed at which the cell could make the transport systems it needs to collect methionine from its surroundings. These findings could prove useful in developing treatments for diseases associated with uncontrollable T cells, such as leukaemia and certain autoimmune diseases. Such treatments could, for example, involve restricting the transport of methionine into T cells through drugs, or potentially via the diet.