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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC].</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR].</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.</jats:p> </jats:sec>

Original publication

DOI

10.1093/ecco-jcc/jjaa054

Type

Journal article

Journal

Journal of Crohn's and Colitis

Publisher

Oxford University Press (OUP)

Publication Date

05/10/2020

Volume

14

Pages

1446 - 1461