T cells in relapsing-remitting multiple sclerosis demonstrate diminished expression of LAG-3

Abstract The co-inhibitory receptor lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates T cell activation, proliferation, and homeostasis. Blockade or deletion of LAG-3 in autoimmune-prone backgrounds or induced-disease models has been shown to exacerbate disease. We observed decreased surface expression of LAG-3 on T cells in subjects with rheumatoid arthritis (n=35), type 1 diabetes (n=105), or relapsing-remitting multiple sclerosis (RRMS; n=121) as compared to age and sex-matched healthy subjects (n=123). Interestingly, decreased LAG-3 expression was observed across CD4 and CD8 T cell subsets. T cell receptor stimulation on a subset of our initial cohort revealed decreased surface and intracellular LAG-3 as well as decreased LAG3 transcript in subjects with RRMS. Decreased LAG-3 in subjects with RRMS was associated with diminished IFNγ production and intracellular cleaved caspase 3; the addition of a LAG-3 blocking antibody further underscored this relationship. Despite the decreased level of LAG-3, CD8 T cells from RRMS subjects were less proliferative than healthy subjects after a low-dose viral peptide stimulation as well as after blocking LAG-3; another indication of defective T cell activation associated with LAG-3 expression. In T cells from RRMS subjects, we observe a global dysregulation of LAG-3 expression that stems from decreased transcription and persists after T cell stimulation. These findings further support the potential clinical benefits of a LAG-3 agonist in the treatment of human autoimmunity.