{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''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.<ref name="Latchman_2001">{{cite journal | vauthors = Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ | title = PD-L2 is a second ligand for PD-1 and inhibits T cell activation | journal = Nature Immunology | volume = 2 | issue = 3 | pages = 261–268 | date = March 2001 | pmid = 11224527 | doi = 10.1038/85330 | s2cid = 27659586 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PDCD1LG2 programmed cell death 1 ligand 2 | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=80380 }}</ref> 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.<ref name="Latchman_2001" /><ref>{{cite journal | vauthors = McDermott DF, Atkins MB | title = PD-1 as a potential target in cancer therapy | journal = Cancer Medicine | volume = 2 | issue = 5 | pages = 662–673 | date = October 2013 | pmid = 24403232 | pmc = 3892798 | doi = 10.1002/cam4.106 }}</ref> PD-L2 is one of two known ligands for Programmed cell death protein 1 (PD-1),<ref name="Latchman_2001" /> the other one being PD-L1 to which it is related by a gene duplication in an ancestor of tetrapod species.<ref>{{cite journal | vauthors = Philips EA, Garcia-España A, Tocheva AS, Ahearn IM, Adam KR, Pan R, Mor A, Kong XP | title = The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals | journal = The Journal of Biological Chemistry | volume = 295 | issue = 14 | pages = 4372–4380 | date = April 2020 | pmid = 31882544 | doi = 10.1074/jbc.AC119.011747 | pmc = 7135984 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hu CB, Huang C, Wang J, Hong Y, Fan DD, Chen Y, Lin AF, Xiang LX, Shao JZ | title = PD-L1/BTLA Checkpoint Axis Exploited for Bacterial Immune Escape by Restraining CD8+ T Cell-Initiated Adaptive Immunity in Zebrafish | journal = Journal of Immunology | volume = 211 | issue = 5 | pages = 816–835 | date = September 2023 | pmid = 37486225 | doi = 10.4049/jimmunol.2300217 }}</ref><ref>{{cite journal | vauthors = Kondo R, Kondo K, Nabeshima K, Nishikimi A, Ishida Y, Shigeoka T, Dijkstra JM | title = PD-1 is conserved from sharks to humans: new insights into PD-1, PD-L1, PD-L2, and SHP-2 evolution | journal = Frontiers in Immunology | volume = 16 | article-number = 1573492 | date = 2025-05-28 | pmid = 40503235 | pmc = 12151841 | doi = 10.3389/fimmu.2025.1573492 | doi-access = free }}</ref>
== Structure == [[File:Highaffinity pdl2 pd1 tang kim.gif|left|thumb|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|link=File:PDL2-PD1highaffinity.gif]]
PD-L2 is a cell surface receptor belonging to the B7 protein family.<ref name="Chen_2004">{{cite journal | vauthors = Chen L | title = Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity | journal = Nature Reviews. Immunology | volume = 4 | issue = 5 | pages = 336–347 | date = May 2004 | pmid = 15122199 | doi = 10.1038/nri1349 | s2cid = 33548210 }}</ref> 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.<ref name="Chen_2004" /> PD-L2 shares considerable sequence homology with other B7 proteins,<ref name="Tseng_2001">{{cite journal | vauthors = Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H | title = B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells | journal = The Journal of Experimental Medicine | volume = 193 | issue = 7 | pages = 839–846 | date = April 2001 | pmid = 11283156 | pmc = 2193370 | doi = 10.1084/jem.193.7.839 }}</ref> but it does not contain the putative binding sequence for CD28/CTLA4, namely SQDXXXELY or XXXYXXRT.<ref name="Tseng_2001" />
The crystal structure of murine PD-L2 bound to murine PD-1 has been determined.<ref>{{cite journal | vauthors = Lázár-Molnár E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC | title = Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 30 | pages = 10483–10488 | date = July 2008 | pmid = 18641123 | pmc = 2492495 | doi = 10.1073/pnas.0804453105 | doi-access = free }}</ref> as well as the structure of the hPD-L2/mutant hPD-1 complex.<ref>{{cite journal | vauthors = Tang S, Kim PS | title = A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 49 | pages = 24500–24506 | date = December 2019 | pmid = 31727844 | pmc = 6900541 | doi = 10.1073/pnas.1916916116 | doi-access = free | bibcode = 2019PNAS..11624500T }}</ref> {{clear|left}}
== Expression ==
=== Profile === PD-L2 is primarily expressed on professional antigen-presenting cells including dendritic cells (DCs) and macrophages.<ref name="Sharpe_2007">{{cite journal | vauthors = Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ | title = The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection | journal = Nature Immunology | volume = 8 | issue = 3 | pages = 239–245 | date = March 2007 | pmid = 17304234 | doi = 10.1038/ni1443 | s2cid = 8749576 }}</ref> Others have shown PD-L2 expression in certain T helper cell subsets and cytotoxic T cells.<ref>{{cite journal | vauthors = Messal N, Serriari NE, Pastor S, Nunès JA, Olive D | title = PD-L2 is expressed on activated human T cells and regulates their function | journal = Molecular Immunology | volume = 48 | issue = 15–16 | pages = 2214–2219 | date = September 2011 | pmid = 21752471 | doi = 10.1016/j.molimm.2011.06.436 | s2cid = 33134166 | url = https://inserm.hal.science/inserm-00600726 }}</ref><ref>{{cite journal | vauthors = Lesterhuis WJ, Steer H, Lake RA | title = PD-L2 is predominantly expressed by Th2 cells | journal = Molecular Immunology | volume = 49 | issue = 1–2 | pages = 1–3 | date = October 2011 | pmid = 22000002 | doi = 10.1016/j.molimm.2011.09.014 }}</ref> PD-L2 protein is widely expressed in many healthy tissues including the GI tract tissues, skeletal muscles, tonsils, and pancreas.<ref name="cited1c0251b">{{cite web | title = Tissue expression of PDCD1LG2 | url = https://www.proteinatlas.org/ENSG00000197646-PDCD1LG2/tissue | work = The Human Protein Atlas | access-date = 2020-03-05 }}</ref> Additionally, PD-L2 has moderate to high expression in triple-negative breast cancer and gastric cancer and low expression in renal cell carcinoma.<ref name="Yearley_2017" /> PD-L2 mRNA is widely expressed and not enriched in any particular tissue.<ref name="cited1c0251b" />
=== Regulation === Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GMCSF) both upregulate PD-L2 expression in DCs ''in vitro''.<ref name="Sharpe_2007" /> IFN-α, IFN-β, and IFN-γ induce moderate upregulation of PD-L2 expression.<ref name="Sharpe_2007" />
== Function == PD-L2 binds to its receptor PD-1 with dissociation constant K<sub>d</sub> of 11.3 nM.<ref name="Ghiotto_2010">{{cite journal | vauthors = Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA, Olive D | title = PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1 | journal = International Immunology | volume = 22 | issue = 8 | pages = 651–660 | date = August 2010 | pmid = 20587542 | pmc = 3168865 | doi = 10.1093/intimm/dxq049 }}</ref> Binding to PD-1 can activate pathways inhibiting TCR/BCR-mediated immune cell activation<ref name="Sharpe_2007" /> (for a more detailed discussion see PD-1 signaling). PD-L2 plays an important role in immune tolerance and autoimmunity.<ref name="Zhang_2006">{{cite journal | vauthors = Zhang Y, Chung Y, Bishop C, Daugherty B, Chute H, Holst P, Kurahara C, Lott F, Sun N, Welcher AA, Dong C | title = Regulation of T cell activation and tolerance by PDL2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 31 | pages = 11695–11700 | date = August 2006 | pmid = 16864790 | pmc = 1544232 | doi = 10.1073/pnas.0601347103 | doi-access = free | bibcode = 2006PNAS..10311695Z }}</ref> Both PD-L1 and PD-L2 can inhibit T cell proliferation and inflammatory cytokine production.<ref name="Ghiotto_2010" /> Blocking PD-L2 has been shown to exacerbate experimental autoimmune encephalomyelitis.<ref name="Zhang_2006" /> 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.<ref name="Ghiotto_2010" /> Others have shown that treatment with PD-L2 Ig led to T helper cell proliferation.<ref name="Zhang_2006" />
== 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.<ref>{{Cite web | title = Search of: PDCD1LG2 - List Results - ClinicalTrials.gov | url = https://clinicaltrials.gov/ct2/results?cond=&term=PDCD1LG2&cntry=&state=&city=&dist= | website = clinicaltrials.gov | language = en | access-date = 2020-03-04 }}</ref>
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.<ref name="Yearley_2017">{{cite journal | vauthors = Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, Lunceford J, Cheng J, Chow LQ, Seiwert TY, Handa M, Tomassini JE, McClanahan T | title = PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer | journal = Clinical Cancer Research | volume = 23 | issue = 12 | pages = 3158–3167 | date = June 2017 | pmid = 28619999 | doi = 10.1158/1078-0432.CCR-16-1761 | doi-access = free }}</ref> In mouse cell cultures, PD-L2 expression on tumor cells suppressed cytotoxic T cell-mediated immune responses.<ref>{{cite journal | vauthors = Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, Kinoshita F, Akiba J, Kashiwagi E, Takeuchi A, Irie T, Tatsugami K, Hoshino T, Eto M, Nishikawa H | title = Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity | journal = Clinical Cancer Research | volume = 25 | issue = 15 | pages = 4808–4819 | date = August 2019 | pmid = 31076547 | doi = 10.1158/1078-0432.CCR-18-3991 | hdl-access = free | doi-access = free | hdl = 2324/4475014 }}</ref>
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.<ref name="Yearley_2017" /> However, PD-L2 does not putatively predict outcome in cancer, with some studies suggesting it predicts negative prognoses<ref>{{cite journal | vauthors = Wang ZL, Li GZ, Wang QW, Bao ZS, Wang Z, Zhang CB, Jiang T | title = PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor | journal = Oncoimmunology | volume = 8 | issue = 2 | date = 2019 | pmid = 30713802 | pmc = 6343813 | doi = 10.1080/2162402X.2018.1541535 | article-number = e1541535 }}</ref><ref>{{cite journal | vauthors = Yang H, Zhou X, Sun L, Mao Y | title = Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis | journal = Frontiers in Oncology | volume = 9 | article-number = 47 | date = 2019 | pmid = 30891423 | pmc = 6413700 | doi = 10.3389/fonc.2019.00047 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tobin JW, Rule G, Colvin K, Calvente L, Hodgson D, Bell S, Dunduru C, Gallo J, Tsang ES, Tan X, Wong J, Pearce J, Campbell R, Tneh S, Shorten S, Ng M, Cochrane T, Tam CS, Abro E, Hawkes E, Hodges G, Kansara R, Talaulikar D, Gilbertson M, Johnston AM, Savage KJ, Villa D, Morris K, Ratnasingam S, Janowski W, Kridel R, Cheah CY, MacManus M, Matigian N, Mollee P, Gandhi MK, Hapgood G | title = Outcomes of stage I/II follicular lymphoma in the PET era: an international study from the Australian Lymphoma Alliance | journal = Blood Advances | volume = 3 | issue = 19 | pages = 2804–2811 | date = October 2019 | pmid = 31570492 | pmc = 6784528 | doi = 10.1200/JCO.18.02365 | doi-access = free }}</ref> and other studies suggesting it predicts positive prognoses.<ref>{{cite journal | vauthors = Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, Bullock TN, Slingluff CL | title = PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome | journal = Oncoimmunology | volume = 5 | issue = 11 | date = 2016 | pmid = 27999753 | pmc = 5139635 | doi = 10.1080/2162402X.2016.1235107 | article-number = e1235107 }}</ref> {{clear}}
== References == {{reflist|32em}}
== Further reading == {{refbegin|32em}} * {{cite journal | vauthors = Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H | title = B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells | journal = The Journal of Experimental Medicine | volume = 193 | issue = 7 | pages = 839–846 | date = April 2001 | pmid = 11283156 | pmc = 2193370 | doi = 10.1084/jem.193.7.839 }} * {{cite journal | vauthors = Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ | title = Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production | journal = Journal of Immunology | volume = 170 | issue = 3 | pages = 1257–1266 | date = February 2003 | pmid = 12538684 | doi = 10.4049/jimmunol.170.3.1257 | doi-access = free }} * {{cite journal | vauthors = Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M | title = Differential binding properties of B7-H1 and B7-DC to programmed death-1 | journal = Biochemical and Biophysical Research Communications | volume = 307 | issue = 3 | pages = 672–677 | date = August 2003 | pmid = 12893276 | doi = 10.1016/S0006-291X(03)01257-9 | bibcode = 2003BBRC..307..672Y }} * {{cite journal | vauthors = Tsushima F, Iwai H, Otsuki N, Abe M, Hirose S, Yamazaki T, Akiba H, Yagita H, Takahashi Y, Omura K, Okumura K, Azuma M | title = Preferential contribution of B7-H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses | journal = European Journal of Immunology | volume = 33 | issue = 10 | pages = 2773–2782 | date = October 2003 | pmid = 14515261 | doi = 10.1002/eji.200324084 | s2cid = 34992725 | doi-access = free }} * {{cite journal | vauthors = Aramaki O, Shirasugi N, Takayama T, Shimazu M, Kitajima M, Ikeda Y, Azuma M, Okumura K, Yagita H, Niimi M | title = Programmed death-1-programmed death-L1 interaction is essential for induction of regulatory cells by intratracheal delivery of alloantigen | journal = Transplantation | volume = 77 | issue = 1 | pages = 6–12 | date = January 2004 | pmid = 14724428 | doi = 10.1097/01.TP.0000108637.65091.4B | s2cid = 25360886 }} * {{cite journal | vauthors = He XH, Liu Y, Xu LH, Zeng YY | title = Cloning and identification of two novel splice variants of human PD-L2 | journal = Acta Biochimica et Biophysica Sinica | volume = 36 | issue = 4 | pages = 284–289 | date = April 2004 | pmid = 15253154 | doi = 10.1093/abbs/36.4.284 | doi-access = free }} * {{cite journal | vauthors = Zhang Z, Henzel WJ | title = Signal peptide prediction based on analysis of experimentally verified cleavage sites | journal = Protein Science | volume = 13 | issue = 10 | pages = 2819–2824 | date = October 2004 | pmid = 15340161 | pmc = 2286551 | doi = 10.1110/ps.04682504 }} * {{cite journal | vauthors = Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y | title = Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer | journal = Clinical Cancer Research | volume = 11 | issue = 8 | pages = 2947–2953 | date = April 2005 | pmid = 15837746 | doi = 10.1158/1078-0432.CCR-04-1469 | doi-access = free }} * {{cite journal | vauthors = Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML | title = PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion | journal = European Journal of Immunology | volume = 35 | issue = 12 | pages = 3561–3569 | date = December 2005 | pmid = 16278812 | doi = 10.1002/eji.200526347 | s2cid = 43876326 | doi-access = free }} * {{cite journal | vauthors = Pfistershammer K, Klauser C, Pickl WF, Stöckl J, Leitner J, Zlabinger G, Majdic O, Steinberger P | title = No evidence for dualism in function and receptors: PD-L2/B7-DC is an inhibitory regulator of human T cell activation | journal = European Journal of Immunology | volume = 36 | issue = 5 | pages = 1104–1113 | date = May 2006 | pmid = 16598819 | pmc = 2975063 | doi = 10.1002/eji.200535344 }} * {{cite journal | vauthors = Abelson AK, Johansson CM, Kozyrev SV, Kristjansdottir H, Gunnarsson I, Svenungsson E, Jönsen A, Lima G, Scherbarth HR, Gamron S, Allievi A, Palatnik SA, Alvarellos A, Paira S, Graf C, Guillerón C, Catoggio LJ, Prigione C, Battagliotti CG, Berbotto GA, García MA, Perandones CE, Truedsson L, Steinsson K, Sturfelt G, Pons-Estel B, Alarcón-Riquelme ME | title = No evidence of association between genetic variants of the PDCD1 ligands and SLE | journal = Genes and Immunity | volume = 8 | issue = 1 | pages = 69–74 | date = January 2007 | pmid = 17136123 | doi = 10.1038/sj.gene.6364360 | doi-access = free }} * {{cite journal | vauthors = Mataki N, Kikuchi K, Kawai T, Higashiyama M, Okada Y, Kurihara C, Hokari R, Kawaguchi A, Nagao S, Kondo T, Itoh K, Miyakawa H, Miura S | title = Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases | journal = The American Journal of Gastroenterology | volume = 102 | issue = 2 | pages = 302–312 | date = February 2007 | pmid = 17311651 | doi = 10.1111/j.1572-0241.2006.00948.x | s2cid = 8083797 }} * {{cite journal | vauthors = Wang SC, Lin CH, Ou TT, Wu CC, Tsai WC, Hu CJ, Liu HW, Yen JH | title = Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus | journal = The Journal of Rheumatology | volume = 34 | issue = 4 | pages = 721–725 | date = April 2007 | pmid = 17343323 | doi = 10.1093/rheumatology/34.8.721 }} {{refend}}
== External links == * {{MeshName|PDCD1LG2+protein,+human}}
{{B7 family|state=collapsed}} {{Clusters of differentiation}}
Category:Clusters of differentiation