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.[4][5] 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.[4][6] PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1).[4]

PDCD1LG2
Identifiers
AliasesPDCD1LG2, B7DC, Btdc, CD273, PD-L2, PDCD1L2, PDL2, bA574F11.2, programmed cell death 1 ligand 2
External IDsOMIM: 605723 MGI: 1930125 HomoloGene: 10973 GeneCards: PDCD1LG2
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9p24.1Start5,510,531 bp[1]
End5,571,282 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

80380

58205

Ensembl

ENSG00000197646

n/a

UniProt

Q9BQ51

Q9WUL5

RefSeq (mRNA)

NM_025239

NM_021396

RefSeq (protein)

NP_079515

NP_067371

Location (UCSC)Chr 9: 5.51 – 5.57 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/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.[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] and other studies suggesting it predicts positive prognoses.[22]

References
  1. GRCh38: Ensembl release 89: ENSG00000197646 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. 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): 261–8. doi:10.1038/85330. PMID 11224527.
  5. "Entrez Gene: PDCD1LG2 programmed cell death 1 ligand 2".
  6. McDermott DF, Atkins MB (October 2013). "PD-1 as a potential target in cancer therapy". Cancer Medicine. 2 (5): 662–73. doi:10.1002/cam4.106. PMC 3892798. PMID 24403232.
  7. Chen L (May 2004). "Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity". Nature Reviews. Immunology. 4 (5): 336–47. doi:10.1038/nri1349. PMID 15122199.
  8. 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): 839–46. doi:10.1084/jem.193.7.839. PMC 2193370. PMID 11283156.
  9. 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): 10483–8. doi:10.1073/pnas.0804453105. PMC 2492495. PMID 18641123.
  10. 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. doi:10.1073/pnas.1916916116. PMC 6900541. PMID 31727844.
  11. 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): 239–45. doi:10.1038/ni1443. PMID 17304234.
  12. 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" (PDF). Molecular Immunology. 48 (15–16): 2214–9. doi:10.1016/j.molimm.2011.06.436. PMID 21752471.
  13. 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.
  14. "Tissue expression of PDCD1LG2". The Human Protein Atlas. Retrieved 2020-03-05.
  15. 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.
  16. Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA, Olive D (August 2010). "PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1". International Immunology. 22 (8): 651–60. doi:10.1093/intimm/dxq049. PMC 3168865. PMID 20587542.
  17. 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): 11695–700. doi:10.1073/pnas.0601347103. PMC 1544232. PMID 16864790.
  18. "Search of: PDCD1LG2 - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-03-04.
  19. 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. PMID 31076547.
  20. Wang ZL, Li GZ, Wang QW, Bao ZS, Wang Z, Zhang CB, Jiang T (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.
  21. 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.
  22. 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.

Further reading
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