Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity

Abstract

Immune responses are highly energy dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. While it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show here that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell-intrinsic and specific to activated effector T cells, as naïve T cells and Treg did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency.

Enhanced biological processes associated with alopecia in polar bears (Ursus maritimus)

“…2013a, 2013b; Iles et al, 2013), it is unlikely to offset nutritional deficiency resulting from lost foraging opportunities on lipid-rich marine mammal prey (Rode et al, 2015). Perhaps simultaneously, increased resource allocation to facilitate extended swimming or foraging bouts due to diminishing sea ice could affect immune function or efficiency (Saucillo et al, 2014). Moreover, nutritional deficiency could mobilize contaminants stored in blubber, further taxing immune function (Letcher et al, 2010) and facilitating disease susceptibility.…”

Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

“…Leptin is a hormone whose primary role is to regulate glucose uptake and fat deposition, and reduced levels thereof have been reported in malnourished individuals (22). Recent data suggest that leptin, in addition to its metabolic functions, is essential for activation of effector T cells (21), and leptin has even been suggested as a potential vaccine adjuvant (49). It would be highly relevant in future TB PEM studies to monitor leptin levels and the potential role of leptin supplementation.…”

“…However, the cellular part of the immune system has, in early studies, been reported to be sensitive to the effects of PEM (15,16), resulting in reduced production of the T helper type 1 (Th1) cytokines gamma interferon (IFN-␥) and interleukin-2 (IL-2) (17)(18)(19)(20). The cellular and molecular background of this reduced response is not fully understood and has been the subject of some debate (21)(22)(23)(24)(25).…”

Differential Impact of Chronic Hyperglycemia on Humoral Versus Cellular Primary Alloimmunity

“…However, confounding immune effects of streptozotocin (12,13) and disrupted leptin signaling (14) complicate interpretation of these studies. Similarly, since autoimmunity can influence alloimmunity (15), the NOD model is also not suitable to address how chronic hyperglycemia itself affects alloimmunity.…”