LAT1 enables T cell activation under inflammatory conditions

The aim of this study was to assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA). Synovial LAT1 expression in RA was monitored by immunohistochemistry and transcriptomic datasets. The contribution of LAT1 to gene expression and immune synapse formation was assessed by RNA-sequencing and total internal reflection fluorescent (TIRF) microscopy, respectively. Mouse models of RA were used to assess the impact of therapeutic targeting of LAT1. LAT1 was strongly expressed by CD4+ T cells in the synovial membrane of people with active RA and the level of expression correlated with levels of ESR and CRP as well as DAS-28 scores. Deletion of LAT1 in murine CD4+ T cells inhibited the development of experimental arthritis and prevented the differentiation of CD4+ T cells expressing IFN-& gamma; and TNF-& alpha;, without affecting regulatory T cells. LAT1 deficient CD4+ T cells demonstrated reduced transcription of genes associated with TCR/CD28 signalling, including Akt1, Akt2, Nfatc2, Nfkb1 and Nfkb2. Functional studies using TIRF mi-croscopy revealed a significant impairment of immune synapse formation with reduced recruitment of CD3 & zeta;and phospho-tyrosine signalling molecules in LAT1 deficient CD4+ T cells from the inflamed joints but not the draining lymph nodes of arthritic mice. Finally, it was shown that a small molecule LAT1 inhibitor, currently undergoing clinical trials in man, was highly effective in treating experimental arthritis in mice. It was concluded that LAT1 plays a critical role in activation of pathogenic T cell subsets under inflammatory conditions and represents a promising new therapeutic target for RA.

Automated summary

The aim of this study was to evaluate the potential therapeutic target of L-type amino acid transporter 1 (LAT1) in rheumatoid arthritis (RA). The study found that LAT1 expression in the synovial membrane of RA patients was strongly associated with disease activity and inflammation indicators. Deletion of LAT1 in mouse CD4+ T cells inhibited the development of arthritis and prevented the differentiation of inflammatory T cell subsets. Furthermore, a small molecule LAT1 inhibitor showed promising results in treating experimental arthritis in mice. In conclusion, LAT1 plays a critical role in the activation of pathogenic T cell subsets in RA and represents a promising therapeutic target.