Type I interferon-dependent CD86(high) marginal zone precursor B cells are potent T cell costimulators in mice.

High levels of expression of type I IFN-inducible genes, known as the “type I IFN” signature, was found in the peripheral blood of SLE patients (1, 2). Type I IFN is produced primarily by CD11clow-expressing dendritic cells (DCs) that express the phenotypic markers B220, Gr-1, and a more specific surface marker, the plasmacytoid dendritic cell antigen (PDCA-1) (3, 4). These DCs are known as plasmacytoid dendritic cells (pDCs) (3–6). T-dependent antibody response requires antigen presentation by major histocompatibility complex II and costimulation via CD80 or CD86 expressed on antigen-presenting cells (7). Studies of human peripheral blood have found increased expression levels of CD80 and CD86 on B cells from SLE patients compared to healthy individuals (8, 9). The severity of lupus disease is positively correlated with the expression levels of CD80 and CD86 (9). However, only CD86 expression was significantly elevated in lupus patients with renal disease, the hallmark of SLE, while differences in CD80 levels were statistically insignificant (10). Other studies have corroborated the importance of CD86 but not CD80 by finding that only CD86 expression on B cells is elevated in patients with inactive SLE and that its level is further elevated in conjunction with active disease (11, 12). We previously demonstrated that BXD2 mice spontaneously produce pathogenic autoantibodies that can induce and exacerbate glomerulonephritis and erosive arthritis (13). Blocking of the interaction of B7-CD28 in young BXD2 mice using AdCTLA4-Ig dramatically suppressed the expression of activation-induced cytidine deaminase (AID), which is the essential enzyme to promote B-cell somatic hypermutation (SHM) and class-switch recombination (CSR) (14). This treatment also prevented the development of both nephritis and arthritis in BXD2 mice (14). Although CD86 was found to be increased in BXD2 B cells (14), it has not been specifically determined if the increased expression of CD86 is associated with the autoimmune pathogenesis in BXD2 mice. It is also unclear as to at what stage(s) of the germinal center (GC) development that CD86high B cells encounter CD28+ CD4 T cells and what mechanisms are involved in driving the encounter of these cells. Recently, we have identified a subpopulation of B cells that have the surface expression of CD1dhighIgMhighCD21highCD23high in BXD2 mice, which are significantly increased in the spleens of BXD2 mice at the expense of reduced marginal zone (MZ) B cell counts (15). This population of CD19+ splenocytes is commonly known as the marginal zone precursor (MZ-P) B cells (16). The immunopathogenesis for MZ-P B cells in BXD2 mice was demonstrated by their high-affinity binding for an exogenous antigen, TNP-Ficoll (15). Importantly, our previous study also showed that high levels of type I IFN produced by pDCs in the marginal sinus plays an important role in upregulating CD69 and facilitating TNP+ MZ-P B-cell migration to the light zone border of GCs (15). In the current study, we examined the role of type I IFN in regulating the surface expression of costimulatory molecules, CD80 and CD86, on follicular (FO), MZ, and MZ-P B cells. We also determined if type I IFN signaling is required for MZ-P localization at the critical T-B border before a spontaneous GC response is initiated. Our present results show that type I IFN-induced upregulation of CD86 on MZ-P B cells and direction of MZ-P migration to the T-B border is important in promoting an IgG antibody response and autoimmune disease.