Inhibitory receptors (IRs) are pivotal in controlling T cell homeostasis because of their intrinsic regulation of conventional effector T (T_conv) cell proliferation, viability, and function. However, the role of IRs on regulatory T cells (T_regs) remains obscure because they could be required for suppressive activity and/or limit T_reg function. We evaluated the role of lymphocyte activation gene 3 (LAG3; CD223) on T_regs by generating mice in which LAG3 is absent on the cell surface of T_regs in a murine model of type 1 diabetes. Unexpectedly, mice that lacked LAG3 expression on T_regs exhibited reduced autoimmune diabetes, consistent with enhanced T_reg proliferation and function. Whereas the transcriptional landscape of peripheral wild-type (WT) and Lag3-deficient T_regs was largely comparable, substantial differences between intra-islet T_regs were evident and involved a subset of genes and pathways that promote T_reg maintenance and function. Consistent with these observations, Lag3-deficient T_regs outcompeted WT T_regs in the islets but not in the periphery in cotransfer experiments because of enhanced interleukin-2–signal transducer and activator of transcription 5 signaling and increased Eos expression. Our study suggests that LAG3 intrinsically limits T_reg proliferation and function at inflammatory sites, promotes autoimmunity in a chronic autoimmune-prone environment, and may contribute to T_reg insufficiency in autoimmune disease.

Immunotherapy targeting coinhibitory receptors has been highly successful in treating a wide variety of malignancies; however, only a subset of patients exhibits durable responses. The first FDA-approved immunotherapeutics targeting coinhibitory receptors PD1 and CTLA4, alone or in combination, significantly improved survival but were also accompanied by substantial toxicity in combination. The third FDA-approved immune checkpoint inhibitor targets LAG3, a coinhibitory receptor expressed on activated CD4+ and CD8+ T cells, especially in settings of long-term antigenic stimulation, such as chronic viral infection or cancer. Mechanistically, LAG3 expression limits both the expansion of activated T cells and the size of the memory pool, suggesting that LAG3 may be a promising target for immunotherapy. Importantly, the mechanism(s) by which LAG3 contributes to CD8+ T-cell exhaustion may be distinct from those governed by PD1, indicating that the combination of anti-LAG3 and anti-PD1 may synergistically enhance antitumor immunity. Clinical studies evaluating the role of anti-LAG3 in combination with anti-PD1 are underway, and recent phase III trial results in metastatic melanoma demonstrate both the efficacy and safety of this combination. Further ongoing clinical trials are evaluating this combination across multiple tumor types and the adjuvant setting, with accompanying translational and biomarker-focused studies designed to elucidate the molecular pathways that lead to improved antitumor T-cell responses following dual blockade of PD1 and LAG3. Overall, LAG3 plays an important role in limiting T-cell activation and has now become part of the repertoire of combinatorial immunotherapeutics available for the treatment of metastatic melanoma.