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 Blood, 15 February 2007, Vol. 109, No. 4, pp. 1773-1781.
Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-02-002386.

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TRANSPLANTATION

B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-{alpha}GAL–producing B-1 cells

Ichiro Shimizu1, Toshiyasu Kawahara1, Fabienne Haspot1, Philip D. Bardwell1, Michael C. Carroll2, and Megan Sykes1

1 Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston; 2 Center for Blood Research, Harvard Medical School, Boston, MA

B-1b cells produce IgM natural antibodies against {alpha}1-3Galß1-4GlcNAc ({alpha}Gal). These can be tolerized by nonmyeloablative induction of mixed chimerism using {alpha}Gal-positive ({alpha}Gal+) donor marrow. We assessed the role of CR1/2 in this model for induction of tolerance of B-1b cells. Mixed hematopoietic chimerism was induced in {alpha}1-3galactosyltransferase (GalT–/–) and GalT–/–Cr2–/– mice with {alpha}Gal+ BALB/c marrow donors. Anti-{alpha}Gal Ab and anti-{alpha}Gal Ab–producing B cells became undetectable in GalT–/– chimeras, whereas they persisted in chimeric GalT–/–Cr2–/– mice. To determine whether CR1/2 expression on stromal cells and/or hematopoietic cells was critical for B-1–cell tolerance, we generated GalT–/– radiation chimeras in which CR1/CR2 was expressed on either stromal cells, hematopoietic cells, neither, or both. After induction of mixed chimerism from {alpha}Gal+ allogeneic bone marrow (BM) donors, anti-{alpha}Gal–producing B cells were rendered tolerant in reconstituted recipients expressing only stromal CR1/CR2. Our results suggest a possible role for follicular dendritic cells that pick up immune complexes via CR1/CR2 receptors in the tolerization of B-1b cells.


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