Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3gene.[5] LAG3, which was discovered in 1990[6] and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000,[7] is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.[8]
Conservation of their respective cytoplasmic tail motifs, CxC/H in the case of CD4 and an ITIM-like motif in the case of LAG-3, supports that competition between CD4 and LAG-3 for binding of kinase LCK is a conserved core part of the jawed vertebrate immune system.
LAG-3 is closely related to CD4,[9] with which it shares the ability to bind MHC class II molecules.[10] Although there has been conflicting information on which motifs in the LAG-3 cytoplasmic tail are important for function,[11][12][13] evolutionary conversation patterns[14][15] combined with functional studies[12][13] imply that the evolutionarily conserved core function of LAG-3 is an inhibitory competition through an immunoreceptor tyrosine-based inhibitory motif (ITIM)–like motif with the activating receptors CD4 or CD8 for binding the kinase LCK.[14]
^Mason D, André P, Bensussan A, Buckley C, Civin C, Clark E, de Haas M, Goyert S, Hadam M, Hart D, Horejsí V, Meuer S, Morrissey J, Schwartz-Albiez R, Shaw S, Simmons D, Uguccioni M, van der Schoot E, Vivier E, Zola H (Nov 2001). "CD antigens 2001". Journal of Leukocyte Biology. 70 (5): 685–90. doi:10.1189/jlb.70.5.685. PMID11698486. S2CID33478518.
^Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID29208439.
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