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IL-6 Contributes to the Expression of RAGs in Human Mature B Cells¹

Laboratory of Immunology, Brest University Medical School Hospital, Brest, France

Mature B cells acquire the capacity to revise rearranged Ig V region genes in secondary lymphoid organs. In previous studies, we demonstrated that cross-linking the BCR and the CD40 induces the expression of the RAG1 and RAG2 enzymes and, thereby, secondary rearrangements. We examine herein the mechanism that underpins RAG1 and RAG2 expression in peripheral and tonsil B cells. Coordinated engagement of the BCR and CD40 promoted the synthesis of IL-6 and, thereby, up-regulation of its receptor on activated B lymphocytes. Furthermore, we provide evidence that IL-6 initiates the expression of RAGs in circulating B cells, and extends those in tonsil B cells. Thus, neutralization of IL-6 or blocking of its receptor inhibits RAG expression. Moreover, we demonstrate that IL-6 impedes BCR-mediated termination of RAG gene expression in both population of B cells. The recovered inhibition of RAG gene transcription by IL-6 receptor blockade supports the notion that once recombination is launched, its termination is also regulated by IL-6. Taken together, these studies provide new insight into the dual role of IL-6 in inducing and terminating expression of the recombinase machinery for secondary rearrangements in mature human B cells.

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 grants from the Communauté Urbaine de Brest, the Conseil Régional de Bretagne, the Académie Nationale Française de Médecine, and the Ministère de l’Enseignement Supérieur et de la Recherche.

² Address correspondence and reprint requests to Prof. Pierre Youinou, Laboratory of Immunology, Brest University Medical School Hospital, BP824, Brest, France. E-mail address: youinou{at}univ-brest.fr

³ Abbreviations used in this paper: BM, bone marrow; SLO, a secondary lymphoid organ; GC, germinal center; LN-PCR, ligation-mediated PCR.

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