LAT1 enables T cell activation under inflammatory conditions: a new therapeutic target for rheumatoid arthritis

Abstract

AbstractObjectiveTo assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA).MethodsSynovial LAT1 expression 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.ResultsLAT1 was strongly expressed by CD4+T cells in the synovial membrane of patients 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-γ and TNF-α, without affecting regulatory T cells. LAT1 deficient CD4+T cells demonstrated reduced transcription of genes associated with TCR/CD28 signalling, includingAkt1, Akt2, Nfatc2, Nfkb1andNfkb2. Functional studies using TIRF microscopy revealed a significant impairment of immune synapse formation with reduced recruitment of CD3ζ 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.ConclusionsIt 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.Key MessagesWhat is already known about this subject?LAT1 is an amino acid transporter that has previously been shown to play a role in T cell activation.What does this study add?LAT1 is expressed by synovial T cells in human rheumatoid arthritis and the level of expression correlates with disease severity.LAT1 expression by T cells is necessary for development of severe arthritis in animal models.LAT1 is required for immune synapse formation and activation of pathogenic CD4+T cell subsets in the inflamed joint, but not the lymph nodes.A small molecular weight LAT1 inhibitor, currently in clinical trials for cancer, is highly effective in animal models of rheumatoid arthritis.How might this impact on clinical practice of future developments?The context-specific nature of LAT1 involvement in T cell activation positions it as an ideal therapeutic target to distinguish between pathogenic and protective T cell responses and this study provides the scientific rationale for clinical evaluation of LAT1 inhibitors in the treatment of rheumatoid arthritis.