Signals that initiate somatic hypermutation of B cells in vitro.
Somatic hypermutation is initiated as B lymphocytes proliferate in germinal centers. The signals that switch on the mutation process are unknown. We have derived an in vitro system to define signals that will initiate mutation in normal, naive splenic B cells. We find that three signals are required to allow detection of somatic mutation in vitro; these are anti-Ig, anti-CD40, and anti-CD38. If any one of these is omitted, mutation remains off. We show that CD40 is obligatory in vivo, as CD40 knockout mice exhibit no Ag-driven mutation. In contrast, CD38 is not, as CD38 knockout mice mutate normally. We believe that, in vitro, CD38, in combination with other stimuli, drives extensive cell division, allowing the detection of mutated sequences. However, in germinal centers in vivo, proliferative activity is instigated by a different molecule. This is the first demonstration of the initiation of hypermutation in vitro with normal splenic B cells using defined stimuli.
Bergthorsdottir
S
S
Department of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Gallagher
A
A
Jainandunsing
S
S
Cockayne
D
D
Sutton
J
J
Leanderson
T
T
Gray
D
D
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D004252:DNA Mutational Analysis; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D018095:Germ-Line Mutation; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009244:NAD+ Nucleosidase / Q000172:deficiency / Q000235:genetics; D010081:Oxazolone / Q000276:immunology; D051381:Rats; D015398:Signal Transduction / Q000276:immunology*; D019076:Transgenes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D008562:Membrane Glycoproteins; D010081:Oxazolone; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1