Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC) is aprotein that in humans is encoded by thePDCD1LG2gene.[5][6] PDCD1LG2 has also been designated asCD273 (cluster of differentiation 273). PDCD1LG2 is animmune checkpoint receptor ligand which plays a role in negative regulation of theadaptive immune response.[5][7] PD-L2 is one of two known ligands forProgrammed cell death protein 1 (PD-1),[5] the other one beingPD-L1 to which it is related by a gene duplication in an ancestor of tetrapod species.[8][9][10]
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 binds to its receptor PD-1 withdissociation constant Kd of 11.3 nM.[20] Binding to PD-1 can activate pathways inhibitingTCR/BCR-mediated immune cell activation[15] (for a more detailed discussion seePD-1 signaling). PD-L2 plays an important role inimmune tolerance andautoimmunity.[21] Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production.[20] Blocking PD-L2 has been shown to exacerbateexperimental autoimmune encephalomyelitis.[21] Unlike PD-L1, PD-L2 has been shown activate the immune system. PD-L2 triggersIL-12 production in murinedendritic cells leading to T cell activation.[20] Others have shown that treatment with PD-L2Ig led toT helper cell proliferation.[21]
The direct role of PD-L2 in cancer progression andimmune-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 suppressedcytotoxic T cell-mediated immune responses.[23]
Indirectly, PD-L2 may have utility as abiomarker or prognostic indicator. PD-L2 expression has been shown to predict response to PD-1 blockade withpembrolizumab independently of PD-L1 expression.[19] However, PD-L2 does not putatively predictoutcome in cancer, with some studies suggesting it predicts negativeprognoses[24][25][26] and other studies suggesting it predicts positive prognoses.[27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abcLatchman 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.PMID11224527.S2CID27659586.
^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.PMID37486225.
^abChen 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.PMID15122199.S2CID33548210.
^abcdSharpe 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.PMID17304234.S2CID8749576.
^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.PMID22000002.
Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, et al. (August 2003). "Differential binding properties of B7-H1 and B7-DC to programmed death-1".Biochemical and Biophysical Research Communications.307 (3):672–677.Bibcode:2003BBRC..307..672Y.doi:10.1016/S0006-291X(03)01257-9.PMID12893276.
Aramaki O, Shirasugi N, Takayama T, Shimazu M, Kitajima M, Ikeda Y, et al. (January 2004). "Programmed death-1-programmed death-L1 interaction is essential for induction of regulatory cells by intratracheal delivery of alloantigen".Transplantation.77 (1):6–12.doi:10.1097/01.TP.0000108637.65091.4B.PMID14724428.S2CID25360886.
Mataki N, Kikuchi K, Kawai T, Higashiyama M, Okada Y, Kurihara C, et al. (February 2007). "Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases".The American Journal of Gastroenterology.102 (2):302–312.doi:10.1111/j.1572-0241.2006.00948.x.PMID17311651.S2CID8083797.
Wang SC, Lin CH, Ou TT, Wu CC, Tsai WC, Hu CJ, et al. (April 2007). "Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus".The Journal of Rheumatology.34 (4):721–725.doi:10.1093/rheumatology/34.8.721.PMID17343323.
