Molecular Medicine; Molecular Biology; Genetics; Cancer Research
Abstract :
[en] CD19 is a central regulator of B-cell biology, acting both as a lineage marker and a critical modulator of signaling thresholds that govern development, activation, and tolerance. Structurally, CD19 is a heavily glycosylated transmembrane protein whose cytoplasmic domain harbors multiple tyrosine motifs serving as docking sites for key signaling molecules, including PI3K. Its expression is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms, as well as by interactions with CD21 and CD81 in surface complexes. Genetic studies in mice and humans demonstrate that CD19 acts as a molecular rheostat, with both deficiency and overexpression leading to profound immunological dysfunctions ranging from hypogammaglobulinemia to autoimmunity. Importantly, recent work has revealed an additional level of CD19 signaling regulation mediated by conformational control of the CD19 cytoplasmic domain. A basic CD19 cytoplasmic juxtamembrane region engages in ionic interactions with PtdIns(4,5)P2, thereby influencing CD19 activation state. Loss of the 5-phosphatase INPP5K increases PtdIns(4,5)P2 levels, leading to constitutive CD19 signaling, impaired B-cell development and hypogammaglobulinemia. This discovery underscores the role of lipid-protein interactions in restraining inappropriate CD19 activation. Clinically, CD19 has emerged as a validated therapeutic target, with CAR T cells, bispecific antibodies, and monoclonal antibodies achieving remarkable efficacy in B-cell malignancies and autoimmune disorders. Understanding the fine regulation of CD19 expression, structure, and signaling remains essential to optimize therapeutic strategies.
Disciplines :
Immunology & infectious disease
Author, co-author :
Schurmans, Stéphane ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF)
F.R.S.-FNRS - Fonds de la Recherche Scientifique FWB - Fédération Wallonie-Bruxelles Fonds Léon Fredericq ULiège - Université de Liège
Funding text :
The authors thank the members of the GIGA-Molecular Biology of Diseases Unit for helpful discussions, the GIGA-In Vitro Imaging (for cell imaging [Sandra Ormenese, Alexandre Hego, and Gaetan Lefevre] and for flow cytometry [Sandra Ormenese, Raafat Stephan, and Celine Vanwinge]) and the GIGA-Mouse Facility platforms at the University of Liege for reagents, discussions, and technical support. B.M. was supported by grants from the FRS-FNRS (Fonds National de la Recherche Scientifique belge; FRIA #2017 and PDR #2020). This work was supported by grants from the Universit\u00E9 de Li\u00E8ge (FRS #2022, #2023 and #2024) (to S.S.), an Actions de Recherche Concert\u00E9e (ARC, F\u00E9d\u00E9ration Wallonie-Bruxelles, #2021\u201325) (to S.S.), the Fonds L\u00E9on Fr\u00E9d\u00E9ricq (to B.M.), and the FRS-FNRS (PDR #2020) (to S.S.).
Aparicio-Pérez, C., Carmona, M., Benabdellah, K., Herrera, C., Failure of ALL recognition by CAR T cells: a review of CD 19-negative relapses after anti-CD 19 CAR-T treatment in B-ALL. Front. Immunol., 14, 2023, 1165870.
Billerhart, M., Hunjadi, M., Hawlin, V., Grünwald-Gruber, C., Maresch, D., Mayrhofer, P., Kunert, R., Recombinant human CD19 in CHO-K1 cells: glycosylation patterns as a quality attribute of high yield processes. Int. J. Mol. Sci., 24, 2023, 10891.
Bradbury, L.E., Kansas, G.S., Levy, S., Evans, R.L., Tedder, T.F., The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J. Immunol. 149 (1992), 2841–2850.
Carter, R.H., Wang, Y., Brooks, S., Role of CD19 signal transduction in B cell biology. Immunol. Res. 26 (2002), 45–54.
Cortés-López, M., Schulz, L., Enculescu, M., Paret, C., Spiekermann, B., Quesnel-Vallières, M., Torres-Diz, M., Unic, S., Busch, A., Orekhova, A., Kuban, M., Mesitov, M., Mulorz, M.M., Shraim, R., Kielisch, F., Faber, J., Barash, Y., Thomas-Tikhonenko, A., Zarnack, K., Legewie, S., König, J., High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance. Nat. Commun., 13, 2022, 5570.
Deaglio, S., Vaisitti, T., Billington, R., Bergui, L., Omede, P., Genazzani, A.A., Malavasi, F., CD38/CD19: a lipid raft-dependent signaling complex in human B cells. Blood 109 (2007), 5390–5398.
Del Nagro, C.J., Otero, D.C., Anzelon, A.N., Omori, S.A., Kolla, R.V., Rickert, R.C., CD19 function in central and peripheral B-cell development. Immunol. Res. 31 (2005), 119–131.
Drokow, E.K., Ahmed, H.A.W., Amponsem-Boateng, C., Akpabla, G.S., Song, J., Shi, M., Sun, K., Survival outcomes and efficacy of autologous CD19 chimeric antigen receptor-T cell therapy in the patient with diagnosed hematological malignancies: a systematic review and meta-analysis. Therapeut. Clin. Risk Manag. 15 (2019), 637–646.
Engel, P., Zhou, L.J., Ord, D.C., Sato, S., Koller, B., Tedder, T.F., Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3 (1995), 39–50.
Fujimoto, M., Poe, J.C., Inaoki, M., Tedder, T.F., CD19 regulates B lymphocyte responses to transmembrane signals. Semin. Immunol. 10 (1998), 267–277.
Fujimoto, M., Poe, J.C., Hasegawa, M., Tedder, T.F., CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification. Immunol. Res. 22 (2000), 281–298.
Fujimoto, M., Fujimoto, Y., Poe, J.C., Jansen, P.J., Lowell, C.A., DeFranco, A.L., Tedder, T.F., CD19 regulates src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 13 (2000), 47–57.
Haas, K.M., Tedder, T.F., Role of the CD19 and CD21/35 receptor complex in innate immunity, host defense and autoimmunity. Adv. Exp. Med. Biol. 560 (2005), 125–139.
Hasegawa, M., Fujimoto, M., Poe, J.C., Steeber, D.A., Tedder, T.F., CD19 can regulate B lymphocyte signal transduction independent of complement activation. J. Immunol. 167 (2001), 3190–3200.
He, X., Hu, B., Zhang, Y., Liu, F., Li, Q., Zheng, C., Shen, J., Yang, Z., Wang, J., Ma, D., Qian, C., Lu, M., Mao, J., Treatment of two pediatric patients with refractory systemic lupus erythematosus using CD19-targeted CAR T-cells. Autoimmun. Rev., 24, 2025, 103692.
Horcher, M., Souabni, A., Busslinger, M., Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 14 (2001), 779–790.
Inaoki, M., Sato, S., Weintraub, B.C., Goodnow, C.C., Tedder, T.F., CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J. Exp. Med. 186 (1997), 1923–1931.
Ishiura, N., Nakashima, H., Watanabe, R., Kuwano, Y., Adachi, T., Takahashi, Y., Tsubata, T., Okochi, H., Tamaki, K., Tedder, T.F., et al. Differential phosphorylation of functional tyrosines in CD19 modulates B-lymphocyte activation. Eur. J. Immunol. 40 (2010), 1192–1204.
Mougiakakos, D., Krönke, G., Völkl, S., Kretschmann, S., Aigner, M., Kharboutli, S., Böltz, S., Manger, B., Mackensen, A., Schett, G., CD19-Targeted CAR T cells in refractory systemic lupus erythematosus. N. Engl. J. Med. 385 (2021), 567–569.
Poe, J.C., Minard-Colin, V., Kountikov, E.I., Haas, K.M., Tedder, T.F., A c-Myc and surface cd19 signaling amplification loop promotes B cell lymphoma development and progression in mice. J. Immunol. 189 (2012), 2318–2325.
Rickert, R.C., Rajewsky, K., Roes, J., Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376 (1995), 352–355.
Rolink, A.G., Schaniel, C., Busslinger, M., Nutt, S.L., Melchers, F., Fidelity and infidelity in commitment to B-lymphocyte lineage development. Immunol. Rev. 175 (2000), 104–111.
Sato, S., Steeber, D.A., Tedder, T.F., The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc. Natl. Acad. Sci. 92 (1995), 11558–11562 U S A.
Sato, S., Ono, N., Steeber, D.A., Pisetsky, D.S., Tedder, T.F., CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J. Immunol. 157 (1996), 4371–4378.
Sato, S., Steeber, D.A., Jansen, P.J., Tedder, T.F., CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19. J. Immunol. 158 (1997), 4662–4669.
Sato, S., CD19 is a central response regulator of B lymphocyte signaling thresholds governing autoimmunity. J. Dermatol. Sci. 22 (1999), 1–10.
Sato, S., Hasegawa, M., Fujimoto, M., Tedder, T.F., Takehara, K., Quantitative genetic variation in CD19 expression correlates with autoimmunity. J. Immunol. 165 (2000), 6635–6643.
Shoham, T., Rajapaksa, R., Boucheix, C., Rubinstein, E., Poe, J.C., Tedder, T.F., Levy, S., The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment. J. Immunol. 171 (2003), 4062–4072.
Sotillo, E., Barrett, D.M., Black, K.L., Bagashev, A., Oldridge, D., Wu, G., Sussman, R., Lanauze, C., Ruella, M., Gazzara, M.R., Martinez, N.M., Harrington, C.T., Chung, E.Y., Perazzelli, J., Hofmann, T.J., Maude, S.L., Raman, P., Barrera, A., Gill, S., Lacey, S.F., Melenhorst, J.J., Allman, D., Jacoby, E., Fry, T., Mackall, C., Barash, Y., Lynch, K.W., Maris, J.M., Grupp, S.A., Thomas-Tikhonenko, A., Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5 (2015), 1282–1295.
Schubert, M.L., Schmitt, A., Hückelhoven-Krauss, A., Neuber, B., Kunz, A., Waldhoff, P., Vonficht, D., Yousefian, S., Jopp-Saile, L., Wang, L., Korell, F., Keib, A., Michels, B., Haas, D., Sauer, T., Derigs, P., Kulozik, A., Kunz, J., Pavel, P., Laier, S., Wuchter, P., Schmier, J., Bug, G., Lang, F., Gökbuget, N., Casper, J., Görner, M., Finke, J., Neubauer, A., Ringhoffer, M., Wolleschak, D., Brüggemann, M., Haas, S., Ho, A.D., Müller-Tidow, C., Dreger, P., Schmitt, M., Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. J. Hematol. Oncol., 16, 2023, 79.
Tedder, T.F., CD19: a promising B cell target for rheumatoid arthritis. Nat. Rev. Rheumatol. 5 (2009), 572–577.
Tedder, T.F., Isaacs, C.M., Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J. Immunol. 143 (1989), 712–717.
Tedder, T.F., Inaoki, M., Sato, S., The CD19–CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity 6 (1997), 107–118.
Teplyakov, A., Obmolova, G., Luo, J., Gilliland, G.L., Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold. Proteins: Struct., Funct., Bioinf. 86 (2018), 495–500.
Tsitsikov, E.N., Gutierrez-Ramos, J.C., Geha, R.S., Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc. Natl. Acad. Sci. USA 94 (1997), 10844–10849.
Velasquez, M.P., Gottschalk, S., Targeting CD19: the good, the bad, and CD81. Blood 129 (2017), 9–10.
van Zelm, M.C., Reisli, I., van der Burg, M., Castano, D., van Noesel, C.J., van Tol, M.J., Woellner, C., Grimbacher, B., Patino, P.J., van Dongen, J.J., et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354 (2006), 1901–1912.
Walter, K., Bonifer, C., Tagoh, H., Stem cell-specific epigenetic priming and B cell-specific transcriptional activation at the mouse Cd19 locus. Blood 112 (2008), 1673–1682.
Wang, K., Wei, G., Liu, D., CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp. Hematol. Oncol., 1, 2012, 36.
Yang, T., Dong, Y., Zhang, M., Feng, J., Fu, S., Xiao, P., Hong, R., Xu, H., Cui, J., Huang, S., Wei, G., Kong, D., Geng, J., Chang, A.H., Huang, H., Hu, Y., Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia. Exp. Hematol. Oncol., 14, 2025, 2.
Zhou, L.J., Ord, D.C., Omori, S.A., Tedder, T.F., Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes. Immunogenetics 35 (1992), 102–111.
Zhou, L.J., Smith, H.M., Waldschmidt, T.J., Schwarting, R., Daley, J., Tedder, T.F., Tissue-specific expression of the human CD19 gene in transgenic mice inhibits antigen-independent B-lymphocyte development. Mol. Cell Biol. 14 (1994), 3884–3894.
