IFN-a/b enhances BCR-dependent B cell responses De  borah Braun 1,2 , Iris Caramalho 1 and Jocelyne Demengeot 1 1 Instituto Gulbenkian de Cie à ncia, Rua da Quinta Grande #6, 2781 Oeiras, Portugal 2 Present address: Laboratoire d'Immunore  gulation, Centre de Recherche du CHUM, Ho à pital Notre-Dame, 1560 Sherbrooke Est., Montre  al H2L4M1 Canada Keywords: B lymphocytes, cellular activation, cytokines, immuno-modulation Abstract Type I interferon (IFN-I) is constitutively produced in the bone marrow (BM), and induced at sites of in¯ammation and following infection by viruses or microorganisms. We have previously shown that IFN-I regulates the generation and selection of normal B cell populations in the BM. In the present work, we assess the effects of IFN-I on mature B cell function by monitoring the responses of IFN-a/b-treated murine splenic B cells to apoptotic, mitogenic and activating stimuli. A similar analysis is performed on BM mature B cells obtained from wild-type or IFN-I receptor-de®cient mice. IFN-a/b is shown to induce B cells to a state of partial activation characterized by the up- regulation of CD69, CD86 and CD25 molecules in the absence of either proliferation or terminal differentiation. B cells treated with IFN-a/b show an increased survival and resistance to Fas- mediated apoptosis. IFN-a/b also enhances B cell responses to BCR ligation such as calcium ¯uxes, IgM internalization, induction of activation markers and proliferation. These results indicate that in addition to its inhibitory effect on viral replication and T cell apoptosis, IFN-a/b plays an essential role during an in¯ammatory response by lowering the threshold for B cell induction, thereby promoting fast and polyclonal antibody responses. Introduction IFN are potent antiviral cytokines produced in response to viral infection. There are two broad categories, called type I (IFN-I) and type II (IFN-II), which were originally distinguished on the basis of the nature of the producing cells. IFN-II is secreted exclusively by NK and T lymphocytes, while IFN-I is produced by a large spectrum of different cell types, mostly components of the innate immune system (1±3). Unlike IFN-II, which is encoded by a single gene, the IFN-g, IFN-I is a family of gene products which differ in structure and expression patterns, but all bind to a single speci®c IFN-I receptor (IFN-IR) (4). In mammals, several IFN-a, and single IFN-b and IFN-w genes encode the various members of IFN-I. Expression of IFN-I follows infection with viruses, mycoplasma and bacteria, and can be experimentally induced by non-infectious agents such as nucleic acids and glucocorticoid hormones (5±8). In turn, IFN-IR ligation induces the expression of numerous genes such as MHC class I, IFN regulatory factor-1, double-stranded RNA-dependent protein kinase, intracellular adhesion mol- ecule-1, oligoadenylate synthetase and MxA, in a large spectrum of different cell types. Most of these proteins promote the elimination of virally infected cells or act as inhibitors of viral replication (1). Although best known for activation of macrophages and NK cells (9,10), IFN-a/b has clear pleiotropic effects on the immune system. In addition to its induction during infection, IFN-I is constitutively produced in primary lymphoid organs (bone marrow and thymus) where it interferes with lymphocyte differentiation (11,12). At early stages of lymphocyte devel- opment, it impairs IL-7-dependent proliferation of pre-B and pre-T cells (13). Later during B cell differentiation, it is responsible for the low threshold of sensitivity to IgM ligation characteristic of both mature and immature B cells in the bone marrow (14). As a direct consequence of this regulation, it determines the stringency of B cell repertoire selection and the number of IgM-secreting B cells in the bone marrow (BM) (15). During an immune response, IFN-a/b also appears to prolong the survival of activated T cells and may promote the generation of memory T cells (16±18). However, studies on resistance to viral infection of mice de®cient for either the IFN- IR (IFN-IR ±/± ) or the IFN-g receptor provided a rough general- Correspondence to: J. Demengeot; E-mail: jocelyne@igc.gulbenkian.pt Transmitting editor: T. Hu Ènig Received 25 June 2001, accepted 17 January 2002 International Immunlogy, Vol. 14, No. 4, pp. 411±419 ã 2002 The Japanese Society for Immunology