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*
Division of Molecular Immunology, Department of Pathology, Weill Medical College of Cornell University, and
The Immunology Program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Partly because of the lack of a suitable in vitro model, the
trigger(s) and the mechanism(s) of somatic hypermutation in Ig genes
are largely unknown. We have analyzed the hypermutation potential of
human CL-01 lymphocytes, our monoclonal model of germinal center B cell
differentiation. These cells are surface IgM+
IgD+ and, in the absence of T cells, switch to IgG, IgA,
and IgE in response to CD40:CD40 ligand engagement and exposure to
appropriate cytokines. We show here that CL-01 cells can be induced to
effectively mutate the expressed VHDJH-Cµ,
VHDJH-C
, VHDJH-C
,
VHDJH-C
, VHDJH-C
,
and V
J-C transcripts before and after Ig class switching in a
stepwise fashion. In these cells, induction of somatic mutations
required cross-linking of the surface receptor for Ag and T cell
contact through CD40:CD40 ligand and CD80:CD28 coengagement. The
induced mutations showed intrinsic features of Ig V(D)J hypermutation
in that they comprised 110 base substitutions (97 in the heavy chain
and 13 in the -chain) and only 2 deletions and targeted V(D)J,
virtually sparing CH and C. These mutations were
more abundant in secondary VHDJH-C than
primary VHDJH-Cµ transcripts and in V(D)J-C
than VJ-C transcripts. These mutations were also associated
with coding DNA strand polarity and showed an overall rate of 2.42
x 10-4 base changes/cell division in
VHDJH-CH transcripts. Transitions
were favored over transversions, and G nucleotides were preferentially
targeted, mainly in the context of AG dinucleotides. Thus, in CL-01
cells, Ig somatic hypermutation is readily inducible by stimuli
different from those required for class switching and displays discrete
base substitution modalities.
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