IFN-γ-producing CD4+ T cells promote generation of protective germinal center-derived IgM+ B cell memory against Salmonella Typhi.
Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland; Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI," Mexican Social Security Institute, Mexico City, C.P. 06020 Mexico;
Christian
C
Perez-Shibayama
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland; Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI," Mexican Social Security Institute, Mexico City, C.P. 06020 Mexico;
Cristina
C
Gil-Cruz
Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, C.P. 04510 Mexico;
Rodolfo
R
Pastelin-Palacios
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland; Department of Pathology, Washington University School of Medicine, St. Louis, MO 63130; Department of Immunology, Washington University School of Medicine, St. Louis, MO 63130; and.
Luisa
L
Cervantes-Barragan
Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI," Mexican Social Security Institute, Mexico City, C.P. 06020 Mexico;
Emiliano
E
Hisaki
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland;
Qian
Q
Chai
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland;
Lucas
L
Onder
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland;
Elke
E
Scandella
Institute for Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
Tommy
T
Regen
Institute for Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
Ari
A
Waisman
Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI," Mexican Social Security Institute, Mexico City, C.P. 06020 Mexico;
Armando
A
Isibasi
Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI," Mexican Social Security Institute, Mexico City, C.P. 06020 Mexico;
Constantino
C
Lopez-Macias
Institute of Immunobiology, Kantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland; burkhard.ludewig@kssg.ch constantino.lopez@imss.gob.mx.
Burkhard
B
Ludewig
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022562:Salmonella Vaccines / Q000235:genetics / Q000276:immunology; D012485:Salmonella typhi / Q000276:immunology*; D014435:Typhoid Fever / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control
C573415:IFNG protein, human; D007075:Immunoglobulin M; D022562:Salmonella Vaccines; D007371:Interferon-gamma