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Mouse Programmed Death Ligand 2 (PD-L2), also named B7DC, CD273, and Butyrophilin-like Protein, is a member of the B7 family of proteins that provide signals for regulating T-cell activation and tolerance (1-4). Other family members include B7-1, B7-2, B7-H2, PD-L1 (B7-H1), and B7-H3. B7 proteins are immunoglobulin (Ig) superfamily members with extracellular Ig-V-like and Ig-C-like domains and short cytoplasmic domains. Among the family members, they share from 20-40% amino acid (aa) sequence identity. The cloned mouse PD-L2 cDNA encodes a 247 aa type I membrane precursor protein with a putative 20 aa signal peptide, a 199 aa extracellular region containing one V-like and one C-like Ig domain, a 23 aa transmembrane region, and only a 5 aa cytoplasmic domain. The extracellular domains of mouse and human PD-L2 share approximately 72% aa sequence identity. PD-L2 is one of two ligands for programmed death-1 (PD-1), a member of the CD28 family of immunoreceptors. The other identified ligand is PD-L1. Mouse PD-L1 and PD-L2 share approximately 34% aa sequence identity and have similar functions. PD-L2 is constitutively expressed in lymphoid and non-lymphoid organs (1-4). The expression of PD-L2 is detected on endothelial cells, dendritic cells (DC), thymic epithelial cells, follicular, memory and regulatory B cells, macrophages and monocytes (1-5). PD-L2 expression is also upregulated in a variety of tumor cell lines. On previously activated T cells, PD-L2 interaction with PD-1 inhibits TCR-mediated proliferation and cytokine production, suggesting an inhibitory role in regulating immune responses. In contrast, a co-stimulatory function for the PD-1 ligands on resting T cells has also been reported. On DC, PD-L2 may promote a Th1 response, while on follicular B cells, PD-L2 would appear to regulate plasma cell and memory B cell generation (6,7).