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From the Centenary Institute for Cancer Medicine and Cell Biology, Newtown, Sydney, New South
Wales, Australia 2042
T-dependent B cell responses in the spleen are initiated in the outer periarteriolar lymphoid
sheath (PALS) and culminate in the generation of proliferative foci and germinal center reactions. By pulsing anti-hen egg lysozyme (HEL) immunoglobulin transgenic (IgTg) B cells with
various concentrations of HEL in vitro before adoptive transfer into normal recipients, it was
shown that a critical number of B cell receptors (BCRs) must be ligated for B cells to undergo
arrest in the outer PALS. T cell help was manipulated independently of the BCR stimulus by
incubating B cells expressing the appropriate major histocompatibility complex class II antigen with a peptide recognized by CD4+ TCR Tg T cells. B cells which either failed to arrest in the outer PALS due to a subthreshold BCR stimulus, or arrested only transiently due to the brevity
of the BCR stimulus, underwent an abortive response within the follicles when provided with
T cell help. In contrast, naive B cells stimulated by a sustained, suprathreshold concentration of
either foreign or self-antigen and given T cell help, proliferated in the outer PALS and then differentiated. Outer PALS arrest was not influenced by the nature of the B cells occupying the
follicle, but appeared to be determined solely by the magnitude of BCR stimulation. Thus antigen-pulsed B cells arrested in the outer PALS in an identical manner irrespective of whether
the follicles comprised a population of normal B cells with multiple specificities, a monoclonal
naive population, or a monoclonal population of tolerant B cells. In addition, tolerant B cells
were found to relocate from the follicles to the outer PALS of HEL/anti-HEL double Tg mice
in which the concentration of soluble self-antigen had been increased by zinc feeding. Similarly, when anti-HEL Tg mice were crossed with a second HEL Tg strain expressing a higher
concentration of soluble HEL, the tolerant anti-HEL Tg B cells were located constitutively in
the outer PALS. Thus, subtle variations in antigen concentration resulted in dramatic changes
in positioning of B cells within the spleen. A series of mixed bone marrow chimeras in which
the effective antigen concentration was inversely related to the number of self-reactive B cells due to
absorption of antigen by transgene-encoded membrane and secreted Ig, was used to confirm that alteration in B cell position previously attributed to changes in follicular composition could be explained on the basis of available antigen concentration, rather than the diversity of the repertoire.
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