Lag3-dependent regulation of microglial functions

About This Grant

Summary The immune co-receptor protein family plays an important role in fine-tuning immune responses. Previous studies have primarily focused on the stimulatory and inhibitory co-receptors expressed by different T cell subsets and their modulatory effects on T cell activation. Inhibitory co-receptors have recently gained significant attention due to their potent ability to reinvigorate T cell responses in the context of chronic infection and cancer. Besides T cells, myeloid lineage cells can express inhibitory co-receptors, and it has been suggested that these receptors may control their activation, potentially interfering with anti-tumor immunity or contributing to neurological disorders. Lymphocyte activation gene 3 (Lag3) is a CD4-like inhibitory co-receptor expressed on various types of T cells, including activated, exhausted, and regulatory T cells. Lag3 is considered a therapeutic target for immune checkpoint blockade to bolster T cell effector functions. We recently reported that Lag3 plays a crucial role in Treg cell functions. Utilizing newly developed Treg cell-specific Lag3-mutant mouse models, we demonstrated that Lag3 expression is essential for adequate Treg cell function to control experimental autoimmune encephalomyelitis (EAE), an autoimmune inflammation in the central nervous system. From analyzing a published single cell RNA sequencing dataset that compare CNS cells between healthy mice and mice with EAE, we unexpectedly found that microglia express high levels of Lag3 even at steady state condition and that the expression level further increases in EAE. Microglial Lag3 expression has previously been proposed to regulate microglia activation in neurological disorders. However, its role in autoimmune neuroinflammation remains explored. In this application, we will use microglia-specific Lag3-mutant mouse models to test the hypothesis that Lag3 regulates microglial functions by promoting their differentiation into anti-inflammatory subsets, thereby modulating autoimmune inflammation. The hypothesis will be tested by the following two specific aims. Aim 1 will test whether microglia Lag3 deficiency influences microglia maintenance at steady state condition and autoimmune disease development. Aim 2 will investigate the mechanism by which Lag3 controls microglial differentiation and functions. The results from this proposal will open new opportunities to investigate the cellular mechanisms through which microglia activation can be modulated by Lag3. Successful completion of this study will identify novel therapeutic opportunities to regulate microglia functions by targeting Lag3.