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Immune Complex-Bearing Follicular Dendritic Cells Deliver a Late Antigenic Signal That Promotes Somatic Hypermutation¹

Yongzhong Wu^2,*, Selvakumar Sukumar^2,*, Mohey Eldin El Shikh^*, Al M. Best, Andras K. Szakal and John G. Tew^3,*

^* Departments of Microbiology and Immunology, Department of Biostatistics, and Department of Anatomy and Neurobiology, and Immunology Group, Virginia Commonwealth University, Richmond, VA 23298

We reasoned that immune complex (IC)-bearing follicular dendritic cells (FDCs) promote somatic hypermutation (SHM). This hypothesis was tested in murine germinal center reactions induced in vitro by coculturing 6-day (4-hydroxy-3-nitrophenyl) acetyl-primed but unmutated ⁺ B cells, chicken -globulin (CGG) memory T cells, FDCs, and ICs (anti-CGG plus NP-CGG). Mutations in primed ⁺ B cells were obtained only when both FDCs and immunogen were present. FDCs alone promoted B cell survival and Ab production but there were no mutations without more immunogen. Moreover, the mutation rate was enhanced when FDCs were activated. Trapped ICs ranged from 200 to 500 Å apart on FDC membranes and this correlated with the periodicity known to optimally signal BCRs. FDCs are unique in their ability to retain ICs for months and a second signal mediated by FDC-ICs appeared to be needed a week or more after immunization by immunogen persisting on FDCs. However, the time needed to detect extensive SHM could be reduced to 7 days if ICs were injected together with memory T cells in vivo. In marked contrast, no mutations were apparent after 7 days in vivo if ICs were replaced by free Ag that would not load on FDCs until Ab was produced. The data suggest that specific Ab production leads to the following events: Ab encounters Ag and ICs are formed, ICs are trapped by FDCs, B cells are stimulated by periodically arranged Ag in ICs on FDCs, and this late antigenic signal promotes SHM.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI-17142.

² Y.W. and S.S. contributed equally to the article.

³ Address correspondence and reprint requests to Dr. John G. Tew, Department of Microbiology and Immunology, Virginia Commonwealth University, P.O. Box 980678, Richmond, VA 23298-0678. E-mail address: tew{at}hsc.vcu.edu

⁴ Abbreviations used in this paper: GC, germinal center; FDC, follicular dendritic cell; IC, immune complex; SHM, somatic hypermutation; NP, (4-hydroxy-3-nitrophenyl) acetyl; CGG, chicken -globulin; EM, electron microscopy; NIP, (4-hydroxy-3-iodo-5-nitrophenyl) acetyl.