Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is a protein that in humans is encoded by the PDCD1LG2 gene. PDCD1LG2 has also been designated as CD273 (cluster of differentiation 273). PDCD1LG2 is an immune checkpoint receptor ligand which plays a role in negative regulation of the adaptive immune response. PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).

Structure

PD-L2 is a cell surface receptor belonging to the B7 protein family. It consists of both an immunoglobulin-like variable domain and an immunoglobulin-like constant domain in the extracellular region, a transmembrane domain, and a cytoplasmic domain. PD-L2 shares considerable sequence homology with other B7 proteins, but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT. The crystal structure of murine PD-L2 bound to murine PD-1 has been determined. as well as the structure of the hPD-L2/mutant hPD-1 complex.

Expression

Profile

PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages. Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells. PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas. Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma. PD-L2 mRNA is widely expressed and not enriched in any particular tissue.

Regulation

Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro. IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.

Function

PD-L2 binds to its receptor PD-1 with dissociation constant Kd of 11.3 nM. Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity. Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production. Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis. Unlike PD-L1, PD-L2 has been shown activate the immune system. PD-L2 triggers IL-12 production in murine dendritic cells leading to T cell activation. Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation.

Clinical significance

PD-L2, PD-L1, and PD-1 expressions are important in the immune response to certain cancers. Due to their role in suppressing the adaptive immune system, efforts have been made to block PD-1 and PD-L1, resulting in FDA approved inhibitors for both (see pembrolizumab, nivolumab, atezolizumab). There are still no FDA approved inhibitors for PD-L2 as of 2019. The direct role of PD-L2 in cancer progression and immune-tumor microenvironment regulation is not as well studied as the role of PD-L1. In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses. Indirectly, PD-L2 may have utility as a biomarker or prognostic indicator. PD-L2 expression has been shown to predict response to PD-1 blockade with pembrolizumab independently of PD-L1 expression. However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses and other studies suggesting it predicts positive prognoses.