was confirmed in 1999 with co-capping experiments and with conventional fluorescence microscopy. In 1999 Triebel showed that LAG-3 could be used as a cancer vaccine, through cancer cell lines transfected with LAG-3. 2000 to 2009. In 2001 the Triebel group identified a LAG3-associated protein, called LAP, that seemed to participate in immune system down-regulation. Also in 2001 the Triebel group reported finding LAG3 expression on CD8+ tumor-infiltrating lymphocytes, with this LAG3 contributing to APC activation. In August 2002 the first phenotypic analysis of the murine LAG-3 was reported by a team at St. Jude Children's Research Hospital in Memphis. Molecular analysis reported by the St. Jude Children's Research Hospital team in November 2002 demonstrated that the inhibitory function of LAG-3 is performed via the protein's cytoplasmic domain. In 2003 the Triebel group was able to identify the MHC class II signal transduction pathways in human dendritic cells induced by LAG3. while the St. Jude Children's Research Hospital team showed that the absence of LAG3 caused no defect in T cell function. In May 2004 the St. Jude Children's Research Hospital team showed, through LAG3 knockout mice, that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool. This was in spite of earlier in vitro work that seemed to suggest that LAG-3 was necessary for T cell expansion. Work at Johns Hopkins University published in October 2004 identified LAG3's key role in regulatory T cells. The St. Jude Children's Research Hospital team reported in December 2004 that LAG-3 is cleaved within the D4 transmembrane domain into two fragments that remain membrane-associated: a 54-kDa fragment that contains all the extracellular domains and oligomerizes with full-length LAG-3 (70 kDa) on the cell surface via the D1 domain, and a 16-kDa peptide that contains the transmembrane and cytoplasmic domains and is subsequently released as soluble LAG-3. In January 2005 scientists at the D'Annunzio University of Chieti–Pescara showed that LAG-3 expression by tumour cells would recruit APCs into the tumour which would have Th1 commitment. Scientists working with AstraZeneca reported in March 2005 that SNPs on LAG3 conferred susceptibility to multiple sclerosis although later work at the Karolinska Institute showed no significant association. In June 2005 the Triebel group showed that antibodies to LAG-3 would result in T cell expansion, through increased rounds of cell division which LAG-3 signalling would otherwise block. In July 2005 scientists at the