inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity. Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies. The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach is GSK2831781 which has entered clinical testing (for plaque psoriasis). History 1990 to 1999 LAG3 was discovered in 1990 by Frédéric Triebel (currently Chief Scientific Officer at Immutep) when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy. An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens while a 1995 paper showed that it bound MHC Class II better than CD4. In 1996 INSERM scientists from Strasbourg showed, in knockout mice that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent. The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997. The phenotype of LAG-3 knockout mice, as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning of natural killer cells but in 1998 Triebel, working with LAG-3 antibodies and soluble protein, found that LAG-3 did not define a specific mode of natural killing. In May 1996 scientists at the University of Florence showed that CD4+ T cells that were LAG-3+ preferentially expressed IFN-γ, and this was up-regulated by IL-12 while in 1997 the same group showed that IFN-γ production was a driver of LAG-3 expression during the lineage commitment of human naive T cells. Subsequent work at the Sapienza University of Rome in 1998 showed that IFN-γ is not required for expression but rather for the up-regulation of LAG-3. The Triebel group in 1998 established that LAG-3 expression on activated human T cells is upregulated by IL-2, IL-7 and IL-12 and also showed that expression of LAG-3 may be controlled by some CD4 regulatory elements. In 1998 the Triebel group showed that, on T cells, LAG-3 down-modulates their proliferation and activation when LAG-3/MHC Class II co-caps with CD3/TCR complex. This relationship