Pharmacological modulation of T helper cell activity currently involves the use of drugs targeting immune receptors or their downstream intracellular signalling pathways. However, there is a growing appreciation of the importance of metabolism-associated environmental cues in fine-tuning T cell activity and this provides novel opportunities for therapeutic intervention. T cells are critically dependent on uptake of amino acids [1], the availability of which exerts a powerful influence on T cell differentiation [[2], [3], [4], [5]]. Uptake of amino acids is regulated by specialised transporters, such as L-type amino acid transporter 1 (LAT1), also known as SLC7A5. LAT1 mediates sodium-independent influx of a range of large neutral amino acids (Leu, Val, Ile, Phe, Trp, His, Met, Tyr) [6] and exists in the plasma membrane as a heterodimeric complex covalently bound to CD98 (SLC3A2) [7]. However, of the two subunits, LAT1 is solely responsible for the transport of amino acids [8] and is expressed by cells with a high nutrient demand [9], such as cancer cells [6,10] and activated T and NK cells [11,12].

Previous work has established the role of LAT1 in the proliferation and differentiation of CD4+ T cells [11] and in this study we set out to evaluate its contribution to the pathogenesis of rheumatoid arthritis (RA), a disease associated with dysregulated T helper cell responses. We first document the presence of LAT1 in the joints of people with RA and then relate its level of expression to clinical and serological markers of disease activity. We next set out to determine the role played by LAT1 in immune synapse formation and T cell activation at the site of inflammation in mice with experimental arthritis. Finally, we use animal models of arthritis to evaluate the efficacy of a small molecule LAT1 inhibitor currently undergoing clinical trials in man. Our findings reveal that LAT1 plays a non-redundant role in activation of specific CD4+ T cell subsets under inflammatory conditions and represents a highly tractable therapeutic target for RA.