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* Transplantation Biology Program and the
Departments of Immunology,
Pediatric and Adolescent Medicine, and
Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905
The control of systemic infection by encapsulated microorganisms requires T-independent type II (TI-2) Ab responses to bacterial polysaccharides. To understand how such responses evolve, we explored the function of transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI), a member of the TNFR family, required for TI-2 Ab production. Quasimonoclonal (QM) mice produce robust TI-2 responses to 4-hydroxy-3-nitrophenylacetate (NP)-Ficoll, owing to the high precursor frequency of NP-specific B cells in the marginal zone of the spleen. QM mice that lack TACI produce decreased numbers of IgM (2-fold) and IgG (1.6-fold) NP-specific ASCs, compared with TACI-positive QM mice in response to immunization with NP-Ficoll. Our studies indicate that TACI acts at a remote time from activation because TACI is not necessary for activation and proliferation of B cells both in vitro and in vivo. Instead, TACI-deficient QM B cells remained in the cell cycle longer than TACI-proficient QM cells and had impaired plasma cell differentiation in response to NP-Ficoll. We conclude that TACI has dual B cell-autonomous functions, inhibiting prolonged B cell proliferation and stimulating plasma cell differentiation, thus resolving the longstanding paradox that TACI may have both B cell-inhibitory and -stimulatory functions. By promoting plasma cell differentiation earlier during clonal expansion, TACI may decrease the chances of autoantibody production by somatic hypermutation of Ig genes in response to T-independent Ags.
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 Grants CA76274, AI48602, AI53733, and HL79067.
2 G.M. and C.C. contributed equally to this work.
3 Address correspondence and reprint requests to Drs. Marilia Cascalho and Richard J. Bram, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. E-mail addresses: cascalho.marilia{at}mayo.edu and bram.richard{at}mayo.edu
4 Abbreviations used in this paper: TI-2, T-independent type 2; QM, quasimonoclonal; NP, 4-hydroxy-3-nitrophenylacetate; TACI, trans-membrane activator calcium modulator and cyclophylin ligand interactor; BLyS, B lymphocyte stimulator; APRIL, a proliferation inducing ligand; KO, knockout; ASC, Ab-secreting cell; Neu5Ac, 
-2,6-linked N-acetylneuraminic acid.
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