PDCD1LG2

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.^[5][6] 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.^[5][7] PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).^[5]

PDCD1LG2
Identifiers
Aliases	PDCD1LG2, B7DC, Btdc, CD273, PD-L2, PDCD1L2, PDL2, bA574F11.2, programmed cell death 1 ligand 2
External IDs	OMIM: 605723; MGI: 1930125; HomoloGene: 10973; GeneCards: PDCD1LG2; OMA:PDCD1LG2 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p24.1 Start 5,510,531 bp[1] End 5,571,282 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 C1 Start 29,388,319 bp[2] End 29,448,561 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium testicle Achilles tendon appendix lymph node spleen gallbladder smooth muscle tissue upper lobe of left lung right lung Top expressed in gastrula embryo submandibular gland thymus mesenteric lymph nodes lumbar spinal ganglion tibiofemoral joint spleen skin of abdomen blood More reference expression data BioGPS More reference expression data
Gene ontology Molecular function molecular function protein binding Cellular component integral component of membrane extracellular region endomembrane system membrane plasma membrane external side of plasma membrane cell surface Biological process negative regulation of activated T cell proliferation T cell costimulation negative regulation of interleukin-10 production negative regulation of T cell proliferation negative regulation of interferon-gamma production immune response positive regulation of T cell proliferation signal transduction cell surface receptor signaling pathway cellular response to lipopolysaccharide adaptive immune response immune system process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 80380 58205 Ensembl ENSG00000197646 ENSMUSG00000016498 UniProt Q9BQ51 Q9WUL5 RefSeq (mRNA) NM_025239 NM_021396 RefSeq (protein) NP_079515 NP_067371 Location (UCSC) Chr 9: 5.51 – 5.57 Mb Chr 19: 29.39 – 29.45 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

X-ray crystallography structure of high affinity mutant hPDL2-hPD1 complex (1.986 Å) reported in Tang and Kim, PNAS 2019. hPD-1: green/blue, hPD-L2: red/orange/yellow

PD-L2 is a cell surface receptor belonging to the B7 protein family.^[8] 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.^[8] PD-L2 shares considerable sequence homology with other B7 proteins,^[9] but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT.^[9]

The crystal structure of murine PD-L2 bound to murine PD-1 has been determined.^[10] as well as the structure of the hPD-L2/mutant hPD-1 complex.^[11]

Expression

Profile

PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages.^[12] Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells.^[13][14] PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas.^[15] Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma.^[16] PD-L2 mRNA is widely expressed and not enriched in any particular tissue.^[15]

Regulation

Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro.^[12] IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.^[12]

Function

PD-L2 binds to its receptor PD-1 with dissociation constant K_d of 11.3 nM.^[17] Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation^[12] (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity.^[18] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production.^[17] Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis.^[18] 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.^[17] Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation.^[18]

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.^[19]

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.^[16] In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses.^[20]

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.^[16] However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses^[21][22][23] and other studies suggesting it predicts positive prognoses.^[24]