{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:42:04Z","timestamp":1790635324278,"version":"4.1.0"},"reference-count":104,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T00:00:00Z","timestamp":1545264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI000615-28"],"award-info":[{"award-number":["AI000615-28"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The \u201cM\u201d in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.<\/jats:p>","DOI":"10.3390\/ijms20010003","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T12:54:36Z","timestamp":1545310476000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Adaptive Immunodeficiency in WHIM Syndrome"],"prefix":"10.3390","volume":"20","author":[{"given":"Shamik","family":"Majumdar","sequence":"first","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1750-1172-7-71","article-title":"Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry","volume":"7","author":"Fenneteau","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","unstructured":"Rath, A., and Wakap, S.N. (2018, December 18). Val\u00e9rie Lanneau Prevalence of Rare Diseases: Bibliographic Data. Orphanet Report Series, Rare Diseases collection, June 2018, Number 1: Diseases Listed in Alphabetical Order. Available online: http:\/\/www.orpha.net\/orphacom\/cahiers\/docs\/GB\/Prevalence_of_rare_diseases_by_diseases.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1182\/blood-2003-10-3532","article-title":"Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome","volume":"104","author":"Gulino","year":"2004","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.jaci.2008.12.1133","article-title":"Clinical and genetic diagnosis of warts, hypogammaglobulinemia, infections, and myelokathexis syndrome in 10 patients","volume":"123","author":"Tassone","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/(SICI)1096-8628(20000424)91:5<368::AID-AJMG10>3.0.CO;2-9","article-title":"WHIM syndrome, an autosomal dominant disorder: Clinical, hematological, and molecular studies","volume":"91","author":"Gorlin","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1182\/blood-2004-06-2289","article-title":"WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12","volume":"105","author":"Balabanian","year":"2005","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1080\/21678707.2017.1375403","article-title":"Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency","volume":"5","author":"Heusinkveld","year":"2017","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng1149","article-title":"Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease","volume":"34","author":"Hernandez","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood-2007-07-102103","article-title":"CXCR4 dimerization and -arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome","volume":"112","author":"Lagane","year":"2008","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.exphem.2005.01.001","article-title":"Enhanced function with decreased internalization of carboxy-terminus truncated CXCR4 responsible for WHIM syndrome","volume":"33","author":"Kawai","year":"2005","journal-title":"Exp. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1158\/1078-0432.CCR-14-0914","article-title":"Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment","volume":"21","author":"Scala","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49212","DOI":"10.1074\/jbc.M207294200","article-title":"\u03b2-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation","volume":"277","author":"Sun","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1056\/NEJM196405072701902","article-title":"Chronic Idiopathic Granulocytopenia","volume":"270","author":"Krill","year":"1964","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJM196404022701402","article-title":"\u201cMyelokathexis\u201d\u2014A New Form of Chronic Granulocytopenia. Report of A Case","volume":"270","author":"Zuelzer","year":"1964","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.cell.2015.01.014","article-title":"Chromothriptic Cure of WHIM Syndrome","volume":"160","author":"McDermott","year":"2015","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10875-017-0457-8","article-title":"Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis","volume":"38","author":"Liu","year":"2018","journal-title":"J. Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/(SICI)1096-8652(199910)62:2<106::AID-AJH8>3.0.CO;2-D","article-title":"Dizygotic twin sisters with myelokathexis: Mechanism of its neutropenia","volume":"62","author":"Taniuchi","year":"1999","journal-title":"Am. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1600-0609.2006.00779.x","article-title":"Recurrent CXCR4 sequence variation in a girl with WHIM syndrome","volume":"78","author":"Alapi","year":"2007","journal-title":"Eur. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.jaci.2005.08.040","article-title":"Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome","volume":"116","author":"Tarzi","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1182\/blood-2017-02-708552","article-title":"How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome","volume":"130","author":"Badolato","year":"2017","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1242\/dev.129.18.4249","article-title":"The chemokine SDF1 regulates migration of dentate granule cells","volume":"129","author":"Bagri","year":"2002","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/31269","article-title":"Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development","volume":"393","author":"Zou","year":"1998","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/31261","article-title":"The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract","volume":"393","author":"Tachibana","year":"1998","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/382635a0","article-title":"Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF\/SDF-1","volume":"382","author":"Nagasawa","year":"1996","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.jpeds.2012.05.058","article-title":"Tetralogy of Fallot is an Uncommon Manifestation of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome","volume":"161","author":"Badolato","year":"2012","journal-title":"J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5722","DOI":"10.1182\/blood-2012-01-403378","article-title":"Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice","volume":"119","author":"Balabanian","year":"2012","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature11885","article-title":"Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches","volume":"495","author":"Ding","year":"2013","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.immuni.2006.10.016","article-title":"Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches","volume":"25","author":"Sugiyama","year":"2006","journal-title":"Immunity"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhang, Y., D\u00e9pond, M., He, L., Foudi, A., Kwarteng, E.O., Lauret, E., Plo, I., Desterke, C., Dessen, P., and Fujii, N. (2016). CXCR4\/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress. Sci. Rep., 6.","DOI":"10.1038\/srep37827"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1084\/jem.20072513","article-title":"CXCR4 is required for the quiescence of primitive hematopoietic cells","volume":"205","author":"Nie","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5663","DOI":"10.1073\/pnas.96.10.5663","article-title":"A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution","volume":"96","author":"Kawabata","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9448","DOI":"10.1073\/pnas.95.16.9448","article-title":"Impaired B.-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice","volume":"95","author":"Ma","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1084\/jem.20160806","article-title":"Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization","volume":"214","author":"Freitas","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3312","DOI":"10.1172\/JCI120375","article-title":"Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model","volume":"128","author":"Gao","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1016\/j.jaci.2016.04.057","article-title":"Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome","volume":"138","author":"Moens","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/ped.13488","article-title":"Neutropenia, hypogammaglobulinemia, and pneumonia: A case of WHIM syndrome","volume":"60","author":"Saettini","year":"2018","journal-title":"Pediatr. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3343\/alm.2017.37.5.446","article-title":"WHIM Syndrome with a Novel CXCR4 Variant in a Korean Child","volume":"37","author":"Shin","year":"2017","journal-title":"Ann. Lab. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1182\/blood-2013-09-527226","article-title":"A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor","volume":"123","author":"McDermott","year":"2014","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1097\/00130832-200312000-00005","article-title":"WHIM syndrome: A genetic disorder of leukocyte trafficking","volume":"3","author":"Gulino","year":"2003","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0014-5793(02)03143-5","article-title":"Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4","volume":"527","author":"Hatse","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"De Clercq, E. (2015). AMD3100\/CXCR4 Inhibitor. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00276"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Liu, T., Li, X., You, S., Bhuyan, S.S., and Dong, L. (2015). Effectiveness of AMD3100 in treatment of leukemia and solid tumors: From original discovery to use in current clinical practice. Exp. Hematol. Oncol., 5.","DOI":"10.1186\/s40164-016-0050-5"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1182\/blood-2011-06-360586","article-title":"The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome","volume":"118","author":"Dale","year":"2011","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1182\/blood-2011-07-368084","article-title":"The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome","volume":"118","author":"McDermott","year":"2011","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.exphem.2005.11.017","article-title":"CXCR4 and CCR5 mediate homing of primitive bone marrow\u2013derived hematopoietic cells to the postnatal thymus","volume":"34","author":"Robertson","year":"2006","journal-title":"Exp. Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7517","DOI":"10.1073\/pnas.1016428108","article-title":"Three chemokine receptors cooperatively regulate homing of hematopoietic progenitors to the embryonic mouse thymus","volume":"108","author":"Calderon","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1182\/blood.V99.2.546","article-title":"Stromal cell-derived factor 1\/CXCR4 signaling is critical for early human T.-cell development","volume":"99","year":"2002","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.4049\/jimmunol.161.6.3103","article-title":"CXCR4 and CCR5 on human thymocytes: Biological function and role in HIV-1 infection","volume":"161","author":"Zaitseva","year":"1998","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.4049\/jimmunol.171.9.4521","article-title":"Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus","volume":"171","author":"Plotkin","year":"2003","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/ni.1830","article-title":"CXCR4 acts as a costimulator during thymic \u03b2-selection","volume":"11","author":"Trampont","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1084\/jem.20091430","article-title":"Thymic development beyond \u03b2-selection requires phosphatidylinositol 3-kinase activation by CXCR4","volume":"207","author":"Janas","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.4049\/jimmunol.170.9.4649","article-title":"A Role of CXC Chemokine Ligand 12\/Stromal Cell-Derived Factor-1\/Pre-B Cell Growth Stimulating Factor and Its Receptor CXCR4 in Fetal and Adult T Cell Development in Vivo","volume":"170","author":"Ara","year":"2003","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lucas, B., White, A.J., Parnell, S.M., Henley, P.M., Jenkinson, W.E., and Anderson, G. (2017). Progressive Changes in CXCR4 Expression That Define Thymocyte Positive Selection Are Dispensable for Both Innate and Conventional \u03b1\u03b2T-cell Development. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-05182-7"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12867","DOI":"10.1073\/pnas.0503603102","article-title":"Glucose transporter 1 expression identifies a population of cycling CD4+CD8+ human thymocytes with high CXCR4-induced chemotaxis","volume":"102","author":"Swainson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1093\/intimm\/10.8.1049","article-title":"Loss of SDF-1 receptor expression during positive selection in the thymus","volume":"10","author":"Suzuki","year":"1998","journal-title":"Int. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1172\/JCI0213853","article-title":"Thymocyte emigration is mediated by active movement away from stroma-derived factors","volume":"109","author":"Poznansky","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5115","DOI":"10.4049\/jimmunol.175.8.5115","article-title":"A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cells from the fetal thymus","volume":"175","author":"Vianello","year":"2005","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.imlet.2008.07.006","article-title":"CXCL12\/CXCR4 signaling promotes human thymic dendritic cell survival regulating the Bcl-2\/Bax ratio","volume":"120","author":"Hernandezlopez","year":"2008","journal-title":"Immunol. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/382829a0","article-title":"The lymphocyte chemoattractant SDF-1 is a ligand for LESTR\/fusin and blocks HIV-1 entry","volume":"382","author":"Bleul","year":"1996","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1126\/science.272.5263.872","article-title":"HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor","volume":"272","author":"Feng","year":"1996","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6928","DOI":"10.1128\/jvi.71.9.6928-6934.1997","article-title":"CXCR4 expression during lymphopoiesis: Implications for human immunodeficiency virus type 1 infection of the thymus","volume":"71","author":"Kitchen","year":"1997","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1128\/JVI.77.10.5784-5793.2003","article-title":"Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4+ Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication","volume":"77","author":"Schmitt","year":"2003","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Salemi, M., Burkhardt, B.R., Gray, R.R., Ghaffari, G., Sleasman, J.W., and Goodenow, M.M. (2007). Phylodynamics of HIV-1 in Lymphoid and Non-Lymphoid Tissues Reveals a Central Role for the Thymus in Emergence of CXCR4-Using Quasispecies. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000950"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1074-7613(00)80046-1","article-title":"The Chemokine Receptor CXCR4 Is Required for the Retention of B Lineage and Granulocytic Precursors within the Bone Marrow Microenvironment","volume":"10","author":"Ma","year":"1999","journal-title":"Immunity"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1002\/eji.201445245","article-title":"CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice: Leukocyte signaling","volume":"45","author":"Liu","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5231","DOI":"10.1073\/pnas.1621512114","article-title":"CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor","volume":"114","author":"Becker","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Roselli, G., Martini, E., Lougaris, V., Badolato, R., Viola, A., and Kallikourdis, M. (2017). CXCL12 Mediates Aberrant Costimulation of B Lymphocytes in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Immunodeficiency. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01068"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1084\/jem.20140457","article-title":"CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow","volume":"211","author":"Beck","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1084\/jem.20041185","article-title":"The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity","volume":"200","author":"Nie","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4837","DOI":"10.1016\/j.vaccine.2010.04.057","article-title":"A quadrivalent HPV vaccine induces humoral and cellular immune responses in WHIM immunodeficiency syndrome","volume":"28","author":"Handisurya","year":"2010","journal-title":"Vaccine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.clim.2010.02.006","article-title":"Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome","volume":"135","author":"Ochs","year":"2010","journal-title":"Clin. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s10875-018-0529-4","article-title":"Transient Marked Increase of \u03b3\u03b4 T Cells in WHIM Syndrome After Successful HSCT","volume":"38","author":"Kawahara","year":"2018","journal-title":"J. Clin. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ni1100","article-title":"Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5","volume":"5","author":"Allen","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.celrep.2016.08.068","article-title":"Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization","volume":"17","author":"Biajoux","year":"2016","journal-title":"Cell. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/j.1600-0609.2009.01368.x","article-title":"Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome","volume":"84","author":"Goda","year":"2010","journal-title":"Eur. J. Haematol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5010","DOI":"10.4049\/jimmunol.164.10.5010","article-title":"Cutting Edge: Stromal Cell-Derived Factor-1 Is a Costimulator for CD4+ T Cell Activation","volume":"164","author":"Nanki","year":"2000","journal-title":"J. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1182\/blood.V99.9.3111","article-title":"Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration","volume":"99","author":"Ticchioni","year":"2002","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.immuni.2006.06.015","article-title":"CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells","volume":"25","author":"Kumar","year":"2006","journal-title":"Immunity"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"ra65","DOI":"10.1126\/scisignal.2004018","article-title":"The chemokine CXCL12 generates costimulatory signals in T cells to enhance phosphorylation and clustering of the adaptor protein SLP-76","volume":"6","author":"Smith","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ni1191","article-title":"T cell costimulation by chemokine receptors","volume":"6","author":"Molon","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10101","DOI":"10.1073\/pnas.0804286105","article-title":"CXCR4-CCR5: A couple modulating T cell functions","volume":"105","author":"Contento","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5954","DOI":"10.4049\/jimmunol.163.11.5954","article-title":"The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes","volume":"163","author":"Sotsios","year":"1999","journal-title":"J. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.4049\/jimmunol.167.4.1857","article-title":"Cutting edge: T cell migration regulated by CXCR4 chemokine receptor signaling to ZAP-70 tyrosine kinase","volume":"167","author":"Ottoson","year":"2001","journal-title":"J. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1182\/blood-2004-03-0843","article-title":"Stromal cell-derived factor-1\/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1","volume":"105","author":"Okabe","year":"2005","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1182\/blood-2012-10-461830","article-title":"The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse","volume":"122","author":"Kallikourdis","year":"2013","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Balabanian, K., Levoye, A., Klemm, L., Lagane, B., Hermine, O., Harriague, J., Baleux, F., Arenzana-Seisdedos, F., and Bachelerie, F. (2008). Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling. J. Clin. Investig.","DOI":"10.1172\/JCI33187"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s10875-016-0276-3","article-title":"WHIM Syndrome Caused by Waldenstr\u00f6m\u2019s Macroglobulinemia-Associated Mutation CXCR4 L329fs","volume":"36","author":"Liu","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.4049\/jimmunol.1400488","article-title":"Cutting Edge: CXCR4 Is Critical for CD8+ Memory T Cell Homeostatic Self-Renewal but Not Rechallenge Self-Renewal","volume":"193","author":"Chaix","year":"2014","journal-title":"J. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1182\/blood-2002-10-3293","article-title":"Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD\/SCID mice","volume":"102","author":"Beider","year":"2003","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6580","DOI":"10.1182\/blood-2011-06-359331","article-title":"Significant mobilization of both conventional and regulatory T cells with AMD3100","volume":"118","author":"Kean","year":"2011","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8451","DOI":"10.1158\/0008-5472.CAN-04-1987","article-title":"Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12\/CXCR4 signals","volume":"64","author":"Zou","year":"2004","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1182\/blood-2010-04-277897","article-title":"CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice","volume":"117","author":"Noda","year":"2011","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4863","DOI":"10.1182\/blood-2011-06-362574","article-title":"Sequential desensitization of CXCR4 and S1P5 controls natural killer cell trafficking","volume":"118","author":"Mayol","year":"2011","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1084\/jem.20111908","article-title":"Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis","volume":"209","author":"Jaeger","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e00645-18","DOI":"10.1128\/mSphereDirect.00645-18","article-title":"Metagenomic discovery of 83 new HPV types in patients with immunodeficiency","volume":"3","author":"Pastrana","year":"2018","journal-title":"mSphere"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.jid.2015.11.004","article-title":"Symptomatic Improvement in Human Papillomavirus-Induced Epithelial Neoplasia by Specific Targeting of the CXCR4 Chemokine Receptor","volume":"136","author":"Meuris","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e1338230","DOI":"10.1080\/2162402X.2017.1338230","article-title":"CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer","volume":"6","author":"Komdeur","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Kim, T.J., Jin, H.-T., Hur, S.-Y., Yang, H.G., Seo, Y.B., Hong, S.R., Lee, C.-W., Kim, S., Woo, J.-W., and Park, K.S. (2014). Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nat. Commun., 5.","DOI":"10.1038\/ncomms6317"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1158\/1535-7163.MCT-15-0742","article-title":"Protection against HPV-16-Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells","volume":"15","author":"Diniz","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1182\/blood-2010-03-272096","article-title":"Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients","volume":"116","author":"Tassone","year":"2010","journal-title":"Blood"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1182\/blood.V130.Suppl_1.995.995","article-title":"X4P-001: A Novel Molecularly-Targeted Oral Therapy for Whim Syndrome","volume":"130","author":"Dale","year":"2017","journal-title":"Blood"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/clpt.2013.58","article-title":"Hematopoietic Stem and Progenitor Cell Mobilization in Mice and Humans by a First-in-Class Mirror-Image Oligonucleotide Inhibitor of CXCL12","volume":"94","author":"Vater","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"23189","DOI":"10.1074\/jbc.M803947200","article-title":"Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12","volume":"283","author":"Balabanian","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1124\/jpet.117.242735","article-title":"CXCR4-Specific Nanobodies as Potential Therapeutics for WHIM syndrome","volume":"363","author":"Heukers","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/1\/3\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:35:09Z","timestamp":1760196909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/1\/3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,20]]},"references-count":104,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["ijms20010003"],"URL":"https:\/\/doi.org\/10.3390\/ijms20010003","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,20]]}}}