PDCD1LG2

Last updated

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
Orthologs
SpeciesHumanMouse
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

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] the other one being PD-L1 to which it is related by a gene duplication in an ancestor of tetrapod species. [8] [9] [10]

Contents

Structure

X-ray crystallography structure of high affinity mutant hPDL2-hPD1 complex (1.986 A) reported in Tang and Kim, PNAS 2019. hPD-1: green/blue, hPD-L2: red/orange/yellow Highaffinity pdl2 pd1 tang kim.gif
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. [11] 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. [11] PD-L2 shares considerable sequence homology with other B7 proteins, [12] but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT. [12]

The crystal structure of murine PD-L2 bound to murine PD-1 has been determined. [13] as well as the structure of the hPD-L2/mutant hPD-1 complex. [14]

Expression

Profile

PD-L2 is primarily expressed on professional antigen presenting cells including dendritic cells (DCs) and macrophages. [15] Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells. [16] [17] PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas. [18] Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma. [19] PD-L2 mRNA is widely expressed and not enriched in any particular tissue. [18]

Regulation

Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs in vitro . [15] IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression. [15]

Function

PD-L2 binds to its receptor PD-1 with dissociation constant Kd of 11.3 nM. [20] Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation [15] (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity. [21] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production. [20] Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis. [21] 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. [20] Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation. [21]

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. [22]

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. [19] In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses. [23]

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. [19] However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses [24] [25] [26] and other studies suggesting it predicts positive prognoses. [27]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000197646 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000016498 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. (March 2001). "PD-L2 is a second ligand for PD-1 and inhibits T cell activation". Nature Immunology. 2 (3): 261–268. doi:10.1038/85330. PMID   11224527. S2CID   27659586.
  6. ↑ "Entrez Gene: PDCD1LG2 programmed cell death 1 ligand 2".
  7. ↑ McDermott DF, Atkins MB (October 2013). "PD-1 as a potential target in cancer therapy". Cancer Medicine. 2 (5): 662–673. doi:10.1002/cam4.106. PMC   3892798 . PMID   24403232.
  8. ↑ Philips EA, Garcia-España A, Tocheva AS, Ahearn IM, Adam KR, Pan R, et al. (April 2020). "The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals". The Journal of Biological Chemistry. 295 (14): 4372–4380. doi: 10.1074/jbc.AC119.011747 . PMC   7135984 . PMID   31882544.
  9. ↑ Hu CB, Huang C, Wang J, Hong Y, Fan DD, Chen Y, et al. (September 2023). "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. doi:10.4049/jimmunol.2300217. PMID   37486225.
  10. ↑ Kondo R, Kondo K, Nabeshima K, Nishikimi A, Ishida Y, Shigeoka T, et al. (2025-05-28). "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 1573492. doi: 10.3389/fimmu.2025.1573492 . PMC   12151841 . PMID   40503235.
  11. 1 2 Chen L (May 2004). "Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity". Nature Reviews. Immunology. 4 (5): 336–347. doi:10.1038/nri1349. PMID   15122199. S2CID   33548210.
  12. 1 2 Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. (April 2001). "B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells". The Journal of Experimental Medicine. 193 (7): 839–846. doi:10.1084/jem.193.7.839. PMC   2193370 . PMID   11283156.
  13. ↑ Lázár-Molnár E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC (July 2008). "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. doi: 10.1073/pnas.0804453105 . PMC   2492495 . PMID   18641123.
  14. ↑ Tang S, Kim PS (December 2019). "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. Bibcode:2019PNAS..11624500T. doi: 10.1073/pnas.1916916116 . PMC   6900541 . PMID   31727844.
  15. 1 2 3 4 Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (March 2007). "The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection". Nature Immunology. 8 (3): 239–245. doi:10.1038/ni1443. PMID   17304234. S2CID   8749576.
  16. ↑ Messal N, Serriari NE, Pastor S, Nunès JA, Olive D (September 2011). "PD-L2 is expressed on activated human T cells and regulates their function". Molecular Immunology. 48 (15–16): 2214–2219. doi:10.1016/j.molimm.2011.06.436. PMID   21752471. S2CID   33134166.
  17. ↑ Lesterhuis WJ, Steer H, Lake RA (October 2011). "PD-L2 is predominantly expressed by Th2 cells". Molecular Immunology. 49 (1–2): 1–3. doi:10.1016/j.molimm.2011.09.014. PMID   22000002.
  18. 1 2 "Tissue expression of PDCD1LG2". The Human Protein Atlas. Retrieved 2020-03-05.
  19. 1 2 3 Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. (June 2017). "PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer". Clinical Cancer Research. 23 (12): 3158–3167. doi: 10.1158/1078-0432.CCR-16-1761 . PMID   28619999.
  20. 1 2 3 Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA, et al. (August 2010). "PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1". International Immunology. 22 (8): 651–660. doi:10.1093/intimm/dxq049. PMC   3168865 . PMID   20587542.
  21. 1 2 3 Zhang Y, Chung Y, Bishop C, Daugherty B, Chute H, Holst P, et al. (August 2006). "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. Bibcode:2006PNAS..10311695Z. doi: 10.1073/pnas.0601347103 . PMC   1544232 . PMID   16864790.
  22. ↑ "Search of: PDCD1LG2 - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-03-04.
  23. ↑ Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, et al. (August 2019). "Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity". Clinical Cancer Research. 25 (15): 4808–4819. doi: 10.1158/1078-0432.CCR-18-3991 . hdl: 2324/4475014 . PMID   31076547.
  24. ↑ Wang ZL, Li GZ, Wang QW, Bao ZS, Wang Z, Zhang CB, et al. (2019). "PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor". Oncoimmunology. 8 (2) e1541535. doi:10.1080/2162402X.2018.1541535. PMC   6343813 . PMID   30713802.
  25. ↑ Yang H, Zhou X, Sun L, Mao Y (2019). "Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis". Frontiers in Oncology. 9 47. doi: 10.3389/fonc.2019.00047 . PMC   6413700 . PMID   30891423.
  26. ↑ Tobin JW, Rule G, Colvin K, Calvente L, Hodgson D, Bell S, et al. (October 2019). "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. doi: 10.1200/JCO.18.02365 . PMC   6784528 . PMID   31570492.
  27. ↑ Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, et al. (2016). "PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome". Oncoimmunology. 5 (11) e1235107. doi:10.1080/2162402X.2016.1235107. PMC   5139635 . PMID   27999753.

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