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Kerstin N. Schmidt^*, Christopher W. Hsu^*, Courtney T. Griffin^*, Christopher C. Goodnow, and Jason G. Cyster^*

From the ^* Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94143; and the Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305

Engagement of antigen receptors on mature B lymphocytes is known to block cell entry into lymphoid follicles and promote accumulation in T cell zones, yet the molecular basis for this change in cell distribution is not understood. Previous studies have shown that follicular exclusion requires a threshold level of antigen receptor engagement combined with occupancy of follicles by B cells without equivalent receptor engagement. The possibility has been raised that follicular composition affects B cell positioning by altering the amount of available antigen and the degree of receptor occupancy. Here we show that follicular composition affects migration of mature B cells under conditions that are independent of antigen receptor occupancy. B cells deficient in the negative regulatory protein tyrosine phosphatase, SHP1, which have elevated intracellular signaling by the B cell receptor, are shown to accumulate in the T zone in the absence of their specific antigen. Follicular exclusion of SHP1–deficient B cells was found to be conditional on the presence of excess B cells that lack elevated intracellular signaling, and was not due to a failure of SHP-1–deficient cells to mature and express the follicle-homing chemokine receptor Burkitt's lymphoma receptor 1. These findings strongly suggest that signals that are negatively regulated by SHP1 promote B cell localization in T cell zones by reducing competitiveness for follicular entry, and provide further evidence that follicular composition influences the positioning of antigen-engaged B cells.

Many thanks to R. Cornall, K. Reif, and A. Weiss for helpful discussions.

K.N. Schmidt is a recipient of a Deutsche Forschungsgemeinschaft postdoctoral fellowship. J.G. Cyster is a Pew Scholar and C.C. Goodnow was supported by the Howard Hughes Medical Institute. This work was supported in part by a grant from the National Institutes of Health (AI-40098-01A1) to J.G. Cyster.

The present address of C.C. Goodnow is Medical Genome Centre & Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, PO Box 334, Mills Rd., The Australian National University, Canberra, ACT 2601, Australia.

Abbreviations used: BLR1, Burkitt's lymphoma receptor 1; CFSE, carboxyfluorescein diacetate succinimidyl ester; HEL, hen egg lysozyme; MBP, mannose-binding protein; me^v, motheaten viable; Rag, recombination-activating gene.

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