Naïve lymphocytes circulate in the body in a resting state, but upon recognition of foreign antigen and receipt of proper costimulatory signals, these cells become activated, undergo a rapid burst in proliferation, and assume effector functions aimed at controlling or killing the invader. There is a growing appreciation that changes in peripheral T cell function are not only supported by but are dependent on metabolic reprogramming and that specific effector functions cannot proceed without adopting the correct metabolism. However, the reasons underlying why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear.

T cell function and fate are dependent on metabolic reprogramming. As T cells differentiate during an immune response, they move from what are presumably nutrient-replete lymphoid organs to sites of cancer or infection, where oxygen, nutrients, growth factors, and other signals may become limiting. These metabolically restrictive environments force T cells to metabolically adapt in order to survive and perform their necessary functions.

Research into the metabolism of tumor cells has provided valuable insight into the metabolic pathways important for cell proliferation and survival, as well as the influence of metabolites themselves on signal transduction and epigenetic programming. Many of these concepts have shaped how we view metabolism in T cells. However, it is important to note that, unlike tumors, T cells rapidly transition between resting catabolic states (naïve and memory T cells) to one of growth and proliferation (effector T cells) as part of a normal developmental program. In addition, as T cells differentiate during an immune response they also move from what are presumably nutrient-replete lymphoid organs to sites of cancer or infection, where oxygen, nutrients, and growth factors may become limiting. Thus, T cells must metabolically adapt to these changing conditions in order to perform their necessary functions. In this review, we highlight emerging areas in the metabolism of these dynamic cells and discuss the potential impact of metabolic control on T cell fate, plasticity, and effector function.

It is becoming increasingly clear that T cell function is intimately linked to metabolic programs, and as such there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. Studying metabolism has often been difficult for the nonexpert, because many of the experimental approaches require specialized instrumentation that has not been widely available. Furthermore, acquiring sufficient cellular material for ex vivo analyses, coupled with the inherent difficulty of assessing cellular metabolism in vivo during an immune response, presents substantial challenges to scientists studying the metabolism of immune cells. Nevertheless, understanding how environmental cues and cellular metabolism influence the outcome of T cell–mediated immune responses will be critical for learning how to exploit metabolism to alter disease outcome. Overall, we are just beginning to understand the pathways that regulate metabolism in lymphocytes and how T cells adapt to changes in their microenvironment, particularly in vivo; this area of immunology is poised for substantial advances in the years to come.