Thursday, November 21, 2024
11/21/2024
Abstract Immune coreceptors play an important role in tuning adaptive T cell responses. Inhibitory receptors have emerged as a target for immune therapy because of their ability to dampen protective immunity in cancers, chronic inflammation, or chronic viral infection. Lymphocyte activation gene-3 (Lag3) is a CD4-like surface co- receptor expressed on the surface of activated lymphocytes. MHCII molecule is the most well characterized Lag3 binding ligand. Lag3-MHCII binding during CD4 T-APC interaction has been shown to inhibit optimal T cell activation. Blocking the interaction with anti-Lag3 antibody or loss-of-function mutant Lag3 renders the T cells to hyper-proliferate and to produce more IL-2. Lag3 has thus emerged as an important immune checkpoint molecule and a potential therapeutic target to reinvigorate anti-tumor immunity. Besides conventional T cells, Foxp3+ regulatory T cells (Tregs), a central regulator of immunity and tolerance, are also known to express high level of Lag3. Many studies demonstrated that Lag3 expression on Tregs is necessary for optimal Treg suppressive function, although there has been a controversial finding that Lag3 instead limits adequate Treg function to control autoimmune diabetes. The precise cellular and molecular mechanisms by which Lag3 controls Treg functions remain largely unknown. During the previous funding period, we uncovered that IL-27 signaling in Tregs is critical for Treg functions to suppress chronic inflammation. We also found that IL-27 induces Lag3 expression in Tregs. By transferring Tregs deficient in Lag3 function, we demonstrated that Lag3 is necessary for Tregs to mitigate chronic autoimmune and allergic inflammation. The overarching goal of this renewal application is to investigate the mechanisms by which Lag3 controls Treg function. We generated novel mouse models in which Lag3 extracellular Ig domain necessary for the function, Lag3 cytoplasmic domain, or Lag3 KIEELE motif is selectively deleted in Tregs and found that the loss-of-function mutation or loss-of-intracellular signal in Tregs drastically impairs Tregs’ ability to suppress autoimmune neuroinflammation. The central hypothesis is that Tregs control inflammatory responses via the Lag3-induced intracellular pathways and that Lag3 regulates Treg metabolic activity. Two specific aims are proposed. Specific Aim 1 will investigate the role of Lag3 in Treg function to control autoimmune inflammation. Specific Aim 2 will investigate the molecular mechanisms by which Lag3 regulates Treg metabolism and functions. Successful completion of the study will not only broaden our understanding Lag3 biology but also identify novel therapeutic strategies targeting Lag3 and its downstream signaling pathways.
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