Lymphocyte activation gene 3 protein (LAG3) is an immune checkpoint receptor that is highly upregulated on exhausted T cells in the tumor microenvironment. LAG3 transmits inhibitory signals to T cells upon binding to MHC class II and other ligands, rendering T cells dysfunctional. Consequently, LAG3 is a major target for cancer immunotherapy with many anti-LAG3 monoclonal antibodies (mAbs) that block LAG3 inhibitory activity in clinical trials. In this review, we examine the molecular basis for LAG3 function in light of recently determined crystal and cryoEM structures of this inhibitory receptor. We review what is known about LAG3 interactions with MHC class II, its canonical ligand, and the newly discovered ligands FGL1 and the T cell receptor (TCR)-CD3 complex, including current controversies over the relative importance of these ligands. We then address the development and mechanisms of action of anti-LAG3 mAbs in clinical trials for cancer immunotherapy. We discuss new strategies to therapeutically target LAG3 using mAbs that not only block the LAG3-MHC class II interaction, but also LAG3 interactions with FGL1 or TCR-CD3, or that disrupt LAG3 dimerization. Finally, we assess the possibility of developing mAbs that enhance, rather than block, LAG3 inhibitory activity as treatments for autoimmune diseases.

Natural killer (NK) cells are essential elements of the innate immune response against tumors and viral infections. NK cell activation is governed by NK cell receptors that recognize both cellular (self) and viral (non‐self) ligands, including MHC, MHC‐related, and non‐MHC molecules. These diverse receptors belong to two distinct structural families, the C‐type lectin superfamily and the immunoglobulin superfamily. NK receptors include Ly49s, KIRs, LILRs, and NKG2A/CD94, which bind MHC class I (MHC‐I) molecules, and NKG2D, which binds MHC‐I paralogs such MICA and ULBP. Other NK receptors recognize tumor‐associated antigens (NKp30, NKp44, NKp46), cell–cell adhesion proteins (KLRG1, CD96), or genetically coupled C‐type lectin‐like ligands (NKp65, NKR‐P1). Additionally, cytomegaloviruses have evolved various immunoevasins, such as m157, m12, and UL18, which bind NK receptors and act as decoys to enable virus‐infected cells to escape NK cell‐mediated lysis. We review the remarkable progress made in the past 25 years in determining structures of representatives of most known NK receptors bound to MHC, MHC‐like, and non‐MHC ligands. Together, these structures reveal the multiplicity of solutions NK receptors have developed to recognize these molecules, and thereby mediate crucial interactions for regulating NK cytolytic activity by self and viral ligands.

Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 in vitro to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.