NGFR regulates stromal cell activation in germinal centers
Alberto Hernández-Barranco,
Vanesa Santos,
Marina S. Mazariegos,
Eduardo Caleiras,
Laura Nogués,
Frédéric Mourcin,
Simon Léonard,
Christelle Oblet,
Steve Genebrier,
Delphine Rossille,
Alberto Benguría,
Alba Sanz,
Enrique Vázquez,
Ana Dopazo,
Alejo Efeyan,
Ana Ortega-Molina,
Michel Cogne,
Karin Tarte,
Héctor Peinado
Affiliations
Alberto Hernández-Barranco
Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain
Vanesa Santos
Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain
Marina S. Mazariegos
Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; Liver Injury and Inflammation Laboratory, Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 28040 Madrid, Spain
Eduardo Caleiras
Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain
Laura Nogués
Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain
Frédéric Mourcin
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France
Simon Léonard
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France
Christelle Oblet
Immunology Department, Faculty of Medicine, Limoges University, CNRS Umr 7276, Inserm U1262, 87000 Limoges, France
Steve Genebrier
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France
Delphine Rossille
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France; SITI Lab, Pôle Biologie, CHU Rennes, 35000 Rennes, France
Alberto Benguría
Genomic Unit, Spanish National Cardiovascular Research, Carlos III, 28029 Madrid, Spain
Alba Sanz
Metabolism and Cell Signaling Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
Enrique Vázquez
Genomic Unit, Spanish National Cardiovascular Research, Carlos III, 28029 Madrid, Spain
Ana Dopazo
Genomic Unit, Spanish National Cardiovascular Research, Carlos III, 28029 Madrid, Spain
Alejo Efeyan
Metabolism and Cell Signaling Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
Ana Ortega-Molina
Metabolism and Cell Signaling Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Metabolism in Cancer and Ageing Laboratory, Immune System and Function Department, Centro de Biología Molecular “Severo Ochoa” (CMBSO-CSIC), Madrid 28049, Spain
Michel Cogne
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France
Karin Tarte
UMR U1236, University Rennes, INSERM, EFS Bretagne, Equipe Labellisée Ligue Contre le Cancer, 35000 Rennes, France; SITI Lab, Pôle Biologie, CHU Rennes, 35000 Rennes, France
Héctor Peinado
Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; Corresponding author
Summary: Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr−/− mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr−/− mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr−/− mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.
