RESEARCH ARTICLE A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis- Induced Gastric MALT Lymphoma Jennifer Gossmann 1 , Manfred Stolte 2 , Michael Lohoff 3 , Philipp Yu 4 , Roland Moll 5 , Florian Finkernagel 6 , Holger Garn 7 , Cornelia Brendel 1 , Alwina Bittner 1¤a , Andreas Neubauer 1 *, Minh Q. Huynh 1¤b 1 Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Hospital Giessen and Marburg, Marburg, Germany, 2 Institute of Pathology, Kulmbach Hospital, Kulmbach, Germany, 3 Institute of Medical Microbiology, Philipps University of Marburg, Marburg, Germany, 4 Institute of Immunology, Philipps University of Marburg, Marburg, Germany, 5 Institute of Pathology, Philipps University of Marburg, Marburg, Germany, 6 Institute of Molecular Biology and Tumor Research, Philipps University of Marburg, Marburg, Germany, 7 Institute of Laboratory Medicine and Pathobiochemistry— Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany ¤a Current address: Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany. ¤b Current address: Landeskrankenhaus Bregenz, Bregenz, Austria. * neubauer@staff.uni-marburg.de Abstract Gastric mucosa-associated lymphoid tissue (MALT) lymphomas develop from a chronic Helicobacter infection. Phospholipase C gamma 2 (PLCG2) is important for B-cell survival and proliferation. We used BALB/c mice with a gain-of-function mutation in the Plcg2 gene (Ali5) to analyze its role in the development of gastric MALT lymphoma. Heterozygous BALB/c Plcg2 Ali5/+ and wildtype (WT) mice were infected with Helicobacter felis (H. felis) and observed up to 16 months for development of gastric MALT lymphomas. In contrast to our initial hypothesis, Plcg2 Ali5/+ mice developed MALT lymphomas less frequently than their WT littermates after long-term infection of 16 months. Infected Plcg2 Ali5/+ mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific IgG1 and IgG2a antibody responses. These results suggested a blunted immune response of Plcg2 Ali5/+ mice towards H. felis infection. Intriguingly, Plcg2 Ali5/+ mice harboured higher numbers of CD73 expressing regulatory T cells (Tregs), possibly responsible for impaired immune response towards Helicobacter infection. We suggest that Plcg2 Ali5/+ mice may be protected from developing gastric MALT lymphomas as a result of elevated Treg numbers, reduced response to H. felis and decrease of proinflammatory cytokines. Introduction Mucosa-associated lymphoid tissue (MALT) lymphomas are extranodal marginal zone B-cell lymphomas. There is a strong association between Helicobacter pylori (H. pylori) infection and PLOS ONE | DOI:10.1371/journal.pone.0150411 March 11, 2016 1 / 17 OPEN ACCESS Citation: Gossmann J, Stolte M, Lohoff M, Yu P, Moll R, Finkernagel F, et al. (2016) A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma. PLoS ONE 11(3): e0150411. doi:10.1371/journal. pone.0150411 Editor: Nupur Gangopadhyay, University of Pittsburgh, UNITED STATES Received: June 20, 2015 Accepted: February 13, 2016 Published: March 11, 2016 Copyright: © 2016 Gossmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by Landes- Offensive zur Entwicklung Wissenschaftlich- ökonomischer Exzellenz (LOEWE) grant “Tumor and Inflammation” (http://www.imt.uni-marburg.de/loewe/, project A1, to AN); research grant of the University Hospital Giessen and Marburg (UKGM, 11/2013 MR, to JG and MQH); Deutsche Forschungsgemeinschaft (KFO 210, NE 310/14-2, to AN and SFB TR22, 491.000., to ML; http://www.dfg.de); José Carreras Leukämie-Stiftung (https://www.carreras-stiftung.de,