Biology:PDCD1LG2

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2] 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.[1][3] PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1),[1] the other one being PD-L1 to which it is related by a gene duplication in an ancestor of tetrapod species.[4][5][6]

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.[7] 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.[7] PD-L2 shares considerable sequence homology with other B7 proteins,[8] but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT.[8]

The crystal structure of murine PD-L2 bound to murine PD-1 has been determined.[9] as well as the structure of the hPD-L2/mutant hPD-1 complex.[10]

Expression

Profile

PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages.[11] Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells.[12][13] PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas.[14] Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma.[15] PD-L2 mRNA is widely expressed and not enriched in any particular tissue.[14]

Regulation

Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro.[11] IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.[11]

Function

PD-L2 binds to its receptor PD-1 with dissociation constant Kd of 11.3 nM.[16] Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation[11] (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity.[17] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production.[16] Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis.[17] 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.[16] Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation.[17]

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.[18]

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.[15] In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses.[19]

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.[15] However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses[20][21][22] and other studies suggesting it predicts positive prognoses.[23]

References

  1. ↑ 1.0 1.1 1.2 "PD-L2 is a second ligand for PD-1 and inhibits T cell activation". Nature Immunology 2 (3): 261–268. March 2001. doi:10.1038/85330. PMID 11224527. 
  2. ↑ "Entrez Gene: PDCD1LG2 programmed cell death 1 ligand 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=80380. 
  3. ↑ "PD-1 as a potential target in cancer therapy". Cancer Medicine 2 (5): 662–673. October 2013. doi:10.1002/cam4.106. PMID 24403232. 
  4. ↑ "The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals". The Journal of Biological Chemistry 295 (14): 4372–4380. April 2020. doi:10.1074/jbc.AC119.011747. PMID 31882544. 
  5. ↑ "PD-L1/BTLA Checkpoint Axis Exploited for Bacterial Immune Escape by Restraining CD8+ T Cell-Initiated Adaptive Immunity in Zebrafish". Journal of Immunology 211 (5): 816–835. September 2023. doi:10.4049/jimmunol.2300217. PMID 37486225. 
  6. ↑ "PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution". Frontiers in Immunology 16. 2025-05-28. doi:10.3389/fimmu.2025.1573492. PMID 40503235. 
  7. ↑ 7.0 7.1 "Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity". Nature Reviews. Immunology 4 (5): 336–347. May 2004. doi:10.1038/nri1349. PMID 15122199. 
  8. ↑ 8.0 8.1 "B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells". The Journal of Experimental Medicine 193 (7): 839–846. April 2001. doi:10.1084/jem.193.7.839. PMID 11283156. 
  9. ↑ "Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2". Proceedings of the National Academy of Sciences of the United States of America 105 (30): 10483–10488. July 2008. doi:10.1073/pnas.0804453105. PMID 18641123. 
  10. ↑ "A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery". Proceedings of the National Academy of Sciences of the United States of America 116 (49): 24500–24506. December 2019. doi:10.1073/pnas.1916916116. PMID 31727844. Bibcode: 2019PNAS..11624500T. 
  11. ↑ 11.0 11.1 11.2 11.3 "The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection". Nature Immunology 8 (3): 239–245. March 2007. doi:10.1038/ni1443. PMID 17304234. 
  12. ↑ "PD-L2 is expressed on activated human T cells and regulates their function". Molecular Immunology 48 (15–16): 2214–2219. September 2011. doi:10.1016/j.molimm.2011.06.436. PMID 21752471. https://inserm.hal.science/inserm-00600726. 
  13. ↑ "PD-L2 is predominantly expressed by Th2 cells". Molecular Immunology 49 (1–2): 1–3. October 2011. doi:10.1016/j.molimm.2011.09.014. PMID 22000002. 
  14. ↑ 14.0 14.1 "Tissue expression of PDCD1LG2". The Human Protein Atlas. https://www.proteinatlas.org/ENSG00000197646-PDCD1LG2/tissue. 
  15. ↑ 15.0 15.1 15.2 "PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer". Clinical Cancer Research 23 (12): 3158–3167. June 2017. doi:10.1158/1078-0432.CCR-16-1761. PMID 28619999. 
  16. ↑ 16.0 16.1 16.2 "PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1". International Immunology 22 (8): 651–660. August 2010. doi:10.1093/intimm/dxq049. PMID 20587542. 
  17. ↑ 17.0 17.1 17.2 "Regulation of T cell activation and tolerance by PDL2". Proceedings of the National Academy of Sciences of the United States of America 103 (31): 11695–11700. August 2006. doi:10.1073/pnas.0601347103. PMID 16864790. Bibcode: 2006PNAS..10311695Z. 
  18. ↑ "Search of: PDCD1LG2 - List Results - ClinicalTrials.gov" (in en). https://clinicaltrials.gov/ct2/results?cond=&term=PDCD1LG2&cntry=&state=&city=&dist=. 
  19. ↑ "Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity". Clinical Cancer Research 25 (15): 4808–4819. August 2019. doi:10.1158/1078-0432.CCR-18-3991. PMID 31076547. 
  20. ↑ "PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor". Oncoimmunology 8 (2). 2019. doi:10.1080/2162402X.2018.1541535. PMID 30713802. 
  21. ↑ "Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis". Frontiers in Oncology 9. 2019. doi:10.3389/fonc.2019.00047. PMID 30891423. 
  22. ↑ "Outcomes of stage I/II follicular lymphoma in the PET era: an international study from the Australian Lymphoma Alliance". Blood Advances 3 (19): 2804–2811. October 2019. doi:10.1200/JCO.18.02365. PMID 31570492. 
  23. ↑ "PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome". Oncoimmunology 5 (11). 2016. doi:10.1080/2162402X.2016.1235107. PMID 27999753. 

Further reading



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