As researchers note here, the LAG-3 receptor on T cells acts as a checkpoint to suppress T cell activity. Like other such receptors that reduce T cell activity, it has been explored in the context of checkpoint inhibitor therapies to treat cancer by preventing tumor-induced reductions in immune activity. Interfering in the activity of LAG-3 was not effective enough in the context of cancer for potential treatments to emerge, but LAG-3 becomes more interesting as a target in autoimmune conditions. It remains to be seen as to whether this will lead to useful therapies, but the data presented here is intriguing.
T cells exhibit both T-cell receptors (TCRs) and checkpoints. TCRs, although shaped so that bits of invading bacteria or viruses fit into them to activate the T cell, are turned on by the body's own proteins in autoimmune diseases. Checkpoints like LAG-3 are also turned on by specific signaling partners, but when this occurs they have the opposite effect of TCRs, suppressing the T cell's activity. TCR-triggering molecules must be presented to T cell receptors by another set of immune cells that ingest foreign (e.g., microbial) or bodily substances in order to display on their surfaces, through protein groups called major histocompatibility complexes (MHC-II), just the small protein pieces that activate a given TCR.
Mechanistically, the research team found that the proximity of LAG-3 lets it loosely stick to part of the T cell receptor called CD3ε (like two oily globs interacting). This attachment was found to pull on CD3ε enough to disrupt its interaction an enzyme called Lck, which is crucial for T cell activation. MHC-II can theoretically attach to LAG-3 and TCR at the same time, but not frequently enough to maximize LAG-3's ability to dial down T cells.
LAG-3 turns off T cells, but less easily due to its spatial requirements than another checkpoint called PD-1. This feature makes LAG-3 inhibitors weaker as anti-cancer cancer treatment than PD-1-inhibiting antibody treatments that have become a mainstay, but likely better when the immune system is overactive, and targeted T cell suppression is required for maximum safe effect. Based on their discovery of the critical role of TCR proximity in LAG-3 function, the research team designed a molecule that enforces LAG-3/TCR proximity to achieve better LAG-3-dependent TCR inhibition and suppression of T cell responses. Their "bi-specific" antibody held LAG-3 and the T cell receptor together more strongly than MHC-II, and without depending on it.
The bispecific antibody, named the LAG-3/TCR Bispecific T cell Silencer or BiTS, potently suppressed T cell responses and lessened inflammatory damage to insulin-producing cells in BiTS-treated mice with a version of Type 1 diabetes. In autoimmune models of hepatitis, BiTS treatment reduced T cell infiltration and liver damage. With the diabetes and hepatitis disease models largely driven by one type of T cells (CD8+), the team also used a mouse model of multiple sclerosis known to be driven by a second major T cell type (CD4+). The team treated mice prone to develop multiple sclerosis with short-term, preventive BiTS prior to the onset of disease symptoms, and BiTS-treated mice had reduced disease by a standard measure.
Link: https://www.eurekalert.org/news-releases/1089253
View the full article at FightAging
