Human plasma C3 is essential for the development of memory B, but not T, lymphocytes

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 3; pp. 1151 - 1154.e14
• Main Authors: Jiménez-Reinoso, Anaïs, Marin, Ana V., Subias, Marta, López-Lera, Alberto, Román-Ortiz, Elena, Payne, Kathryn, Ma, Cindy S., Arbore, Giuseppina, Kolev, Martin, Freeley, Simon J., Kemper, Claudia, Tangye, Stuart G., Fernández-Malavé, Edgar, Rodríguez de Córdoba, Santiago, López-Trascasa, Margarita, Regueiro, José R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2018; Elsevier Limited
• Subjects: Blood plasma; Dendritic cells; Homeostasis; Immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Meningitis; Mutation; Parvoviruses; Patients; Plasma; Pneumonia; Regulation; T cell receptors
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.09.037

[...]we generated pure T- and B-cell lines from our cohort and analyzed their intracellular C3 content by flow cytometry using specific mAb against 2 C3-associated neoepitopes (see Fig E4 in this article's Online Repository at www.jacionline.org). Analysis and gating strategy for CD8+ T-cell subsets was performed as previously described.E4,E5 Proliferation in response to mitogens and antibody titers PBMCs were stained with carboxyfluorescein succinimidyl ester (from Molecular Probes, Eugene, Ore) and cultured in RPMI-1640 supplemented with 10% FBS for 5 days after stimulation with 1 μg/mL plate-coated anti-CD3 (UCHT-1, OKT3; eBioscience, Waltham, Mass), 5 μg/mL Phaseolus vulgaris leucoagglutinin (PHA), 10 ng/mL phorbol 12-myristate 13-acetate and 1 μM ionomycin, 8 μg/mL Phytolacca americana pokeweed mitogen (PWM) (Sigma-Aldrich, St Louis, Mo), or 10 ng/mL superantigens (Staphylococcal Enterotoxin B or E; Toxin Technology, Inc, Sarasota, Fla). Generation of transformed T- and B-cell lines Human T-cell lymphotropic virus type 1-transformed T-cell lines, which have been reported to synthesize higher intracellular C3 than resting or activated primary T cells,E7 were generated as reported,E8 and maintained in RMPI-1640 supplemented with 10% FBS, 1% l-glutamine, 1% Antibiotic-Antimycotic (Gibco, Waltham, Mass), and 100 IU/mL recombinant human IL-2 (provided by Craig W. Reynolds, Frederick Cancer Research and Development Center, National Cancer Institute, National Institutes of Health, Frederick, Md). Code Plasma C3 deficiency Age (y) Main renal pathology Renal dysfunction stage‡ Other pathologies Infections§ Current condition % Memory B cells|| AD∗ PA† Unswitched Switched C3.1.II:1 Primary 9 18 MPGN I 1 HSPArthralgia Pneumonia (x2) Normal renal functionMild proteinuria 2.40 1.70 C3.2.II:1 Primary 1 13 MPGN I 1 HSPHemolytic anemiaChronic hemolysisSplenomegaly Streptoccocal pharingytisViral meningitis, B19 parvovirus Normal renal functionChronic hemolysisSplenomegaly 8.70 6.50 C3.3.II:2 Secondary 23 40 C3G 3 HSPHypertensionHypercholesterolemia SepticemiaPneumonia ProteinuriaMild hematuria 8.40 7.90 C3.4.I:1 Secondary 45 49 - 1 - - Asymptomatic 6.54 22.40 CFI.1.II.1 Secondary 23 39 - - - Meningococcal septicemiaMeningococcal meningitis Asymptomatic 4.20 3.90 CFI.1.II.4 Secondary 14 30 - - - Meningitis Asymptomatic 3.70 4.70 CFI.2.II:2 Secondary 19 53 - - HSPChronic juvenile arthritis Meningococcal meningitisPneumococcal pneumonia Asymptomatic 5.67 12.88 1 E.S. Reis, D.A. Falcão, L. Isaac, Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H, Scand J Immunol, Vol. 63, 2006, 155-168 2 A.K. Matsumoto, D.R. Martin, R.H. Carter, L.B. Klickstein, J.M. Ahearn, D.T. Fearon, J Exp Med, Vol. 178, 1993, 1407-1417 3 P.W. Dempsey, M.E. Allison, S. Akkaraju, C.C. Goodnow, D.T. Fearon, C3d of complement as a molecular adjuvant: bridging innate and acquired immunity, Science, Vol. 271, 1996, 348-350 4 A. Ghannam, M. Pernollet, J.L. Fauquert, N. Monnier, D. Ponard, M.B. Villiers, Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells, J Immunol, Vol. 181, 2008, 5158-5166 5 Y. Okura, I. Kobayashi, M. Yamada, S. Sasaki, Y. Yamada, I. Kamioka, Clinical characteristics and genotype-phenotype correlations in C3 deficiency, J Allergy Clin Immunol, Vol. 137, 2016, 640-644.e1 6 M.K. Liszewski, M. Kolev, G. Le Friec, M. Leung, P.G. Bertram, A.F. Fara, Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation, Immunity, Vol. 39, 2013, 1143-1157 7 C. Théry, M. Ostrowski, E. Segura, Membrane vesicles as conveyors of immune responses, Nat Rev Immunol, Vol. 9, 2009, 581-593 8 C. Hess, C. Kemper, Complement-mediated regulation of metabolism and basic cellular processes, Immunity, Vol. 45, 2016, 240-254