Updated project metadata. Sialic acid-binding Ig-like lectin 15 (Siglec-15) is emerging as an immune modulator and target for cancer immunotherapy. However, limited knowledge regarding its mechanism of action and structure, or its binding partners with T cells, restrains the development of drug candidates that could unleash its full therapeutic potential. Here, we determine the crystal structure of Siglec-15 and delineate its binding epitope by co-crystallization with an anti-Siglec-15 blocking antibody. Saturation transfer-difference nuclear magnetic resonance (STD-NMR) spectroscopy assisted with molecular dynamics simulations reveals the binding mode of Siglec-15 to (2,3)- and 2,6)- linked sialic acids and to the cancer-associated sialyl-Tn (STn) glycoform. Binding of Siglec-15 to T cells, which lack STn expression, depends on the presence of (2,3)- and 2,6)- linked sialoglycans. We identify the leukocyte integrin CD11b as a binding partner of Siglec-15 on human T cells. Collectively, these data provide an integrative understanding of the structural features of Siglec-15 and underscore glycosylation as an additional layer of control of T cell responses.