Lag3 supports Treg function through its conserved KIEELE motif 4128

Description Lymphocyte activation gene-3 (Lag3) is an inhibitory receptor currently undergoing clinical trials for cancer treatment. While the primary function of Lag3 is to inhibit conventional T cell activation, its role in Tregs remains unclear. Understanding the precise biology of Lag3 is thus of significant importance. We recently reported that Lag3 supports Treg function by modulating metabolism. Lag3-/- Tregs exhibit defects in their suppressive function in EAE. These mutant Tregs also show an altered metabolic profile, with increased Myc expression and enhanced glycolytic activity. We also found that the cytoplasmic domain of Lag3 is critical for both Treg function and metabolism, highlighting the importance of Lag3-induced intracellular signaling. However, the molecular mechanisms underlying this process remain unclear. KIEELE is a conserved six-amino acid motif in Lag3, previously shown to be required for Lag3 signaling in vitro. Here, we report that the KIEELE motif is also required for regulating Treg function in vivo. With a new mouse model where the KIEELE motif is specifically absent in Tregs, we found that Treg-specific Lag3 KIEELE-mutant mice develop severe EAE. KIEELE-mutant Tregs also exhibit altered metabolic profiles and reduced suppressive functions, similar to those seen in our previous studies on Lag3-mutant Tregs. Thus, our study demonstrates, for the first time, that Lag3 KIEELE motif is crucial for Lag3-mediated regulation of Treg function.