Abstract Protein-carbohydrate interactions are essential in maintaining immune homeostasis and orchestrating inflammatory and regulatory immune processes. This review elucidates the immune interactions of macrophage galactose-type lectin (MGL, CD301) and Tn carbohydrate antigen. MGL is a C-type lectin receptor (CLR) primarily expressed by myeloid cells such as macrophages and immature dendritic cells. MGL recognizes terminal O-linked N-acetylgalactosamine (GalNAc) residue on the surface proteins, also known as Tn antigen (Tn). Tn is a truncated form of the elongated cell surface O-glycan. The hypoglycosylation leading to Tn may occur when the enzyme responsible for O-glycan elongation—T-synthase—or its associated chaperone—Cosmc—becomes functionally inhibited. As reviewed here, Tn expression is observed in many different neoplastic and non-neoplastic diseases, and the recognition of Tn by MGL plays an important role in regulating effector T cells, immune suppression, and the recognition of pathogens.