The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 10 April 2006 doi:10.1084/jem.20060087
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 1081-1091
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ARTICLE

 Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation

Didrik Paus1,2, Tri Giang Phan1,2, Tyani D. Chan1,2, Sandra Gardam1,2, Antony Basten1,2, and Robert Brink1,2

1 Centenary Institute of Cancer Medicine and Cell Biology, Newtown NSW 2042, Australia
2 Faculty of Medicine, University of Sydney, Camperdown NSW 2006, Australia

CORRESPONDENCE Robert Brink: r.brink{at}garvan.org.au

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.

Abbreviations used: BCR, B cell receptor; CGG, chicken {gamma}-globulin; GC, germinal center; HEL, hen egg lysozyme; NP, (4-hydroxy-3-nitrophenyl)acetyl; SHM, somatic hypermutation, SRBC, sheep red blood cells; TI-2, T-independent type 2.

D. Paus and T.G. Phan contributed equally to this paper.

T.G. Phan's present address is Dept. of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.

T.D. Chan's, S. Gardam's, and R. Brink's present address is Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.


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