LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Abstract

Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

A Combined Omics Approach to Generate the Surface Atlas of Human Naive CD4+ T Cells during Early T-Cell Receptor Activation

“…In the current human study, this surface transporter protein was also among the top significantly regulated hits on RNA as well as on protein level. SLC7A5 showed a strong up-regulation upon the general ␣CD3/␣CD28 TCR stimulus like it was previously shown for CD4 ϩ /CD25 Ϫ T cells (49). Further members of the SLC family, (SLC4A2-Anion exchanger 2, SLC2A3-GLUT-3, SLC29A1-equilibrative nucleoside transporter 1,…”

T cell metabolism drives immunity

“…Inhibition of PDK1 using dichloroacetate (DCA) selectively impairs Th17 proliferation and survival and reduces T cell-mediated inflammation in models of inflammatory bowel disease and EAE . Targeting trophic transporters on T cells may also provide a way in which to manipulate T cell function through altering their nutrient uptake; for example, JPH203, which inhibits amino acid transporter Slc7a5, could be used to inhibit inflammatory T cells without impairing T reg cell function (Hayashi et al, 2013;Sinclair et al, 2013). In the context of cancer, the development of adoptive cellular immunotherapies using in vitro-expanded tumor infiltrating lymphocytes (TILs) could benefit from tailoring culture conditions to optimize TIL metabolism before transfer into the patient (Restifo et al, 2012).…”

LAT1 Is a Central Transporter of Essential Amino Acids in Human Umbilical Vein Endothelial Cells

“…However, we have to consider quite carefully about the utility of LAT1 inhibitor in clinical practice, since we cannot exclude the possibility that LAT1 functions in normal blood vessels. Nonetheless, we presume that the blood vessels in cancer tissue express higher level of LAT1 compared to normal blood vessels, since LAT1 is preferentially expressed in proliferating cells such as cancer and activated T cells (4). If such is the case, JPH203 could be an attractive drug for clinical therapy by selectively preventing angiogenesis in a lesion area but not in normal tissues.…”