The influence of effector T cells and Fas ligand on lupus-associated B cells

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The Journal of Immunology (Impact Factor: 4.92). 08/2005; 175(1):104-11. DOI: 10.4049/jimmunol.175.1.104
Source: PubMed

ABSTRACT Circulating autoantibodies against dsDNA and chromatin are a characteristic of systemic lupus erythematosus in humans and many mouse models of this disease. B cells expressing these autoantibodies are normally regulated in nonautoimmune-prone mice but are induced to secrete Abs following T cell help. Likewise, anti-chromatin autoantibody production is T cell-dependent in Fas/Fas ligand (FasL)-deficient (lpr/lpr or gld/gld) mice. In this study, we demonstrate that Th2 cells promote anti-chromatin B cell survival and autoantibody production in vivo. FasL influences the ability of Th2 cells to help B cells, as Th2-gld/gld cells support higher titers of anti-chromatin Abs than their FasL-sufficient counterparts and promote anti-chromatin B cell participation in germinal centers. Th1 cells induce anti-chromatin B cell germinal centers regardless of FasL status; however, their ability to stimulate anti-chromatin Ab production positively correlates with their level of IFN-gamma production. This distinction is lost if FasL-deficient T cells are used: Th1-gld/gld cells promote significant titers of anti-chromatin Abs regardless of IFN-gamma production levels. Thus, FasL from effector T cells plays an important role in determining the fate of anti-chromatin B cells.

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Available from: Michele L Fields, Nov 05, 2014
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    • "The importance of T cell-B cell interaction has been demonstrated in lupus-prone MRL-lpr animals lacking CD4 + or ab T cells, because these animals have delayed, less-severe disease and reduced autoantibody titers (Connolly et al., 1992; Peng, 1998; Peng et al., 1996b). Conversely, the addition of autoreactive T cells to preautoimmune or nonautoimmune mice has led to autoreactive B cell activation and autoantibody secretion (Adams et al., 1991; Ando et al., 1987; Fields et al., 2005b) and even loss of anergic features (Seo et al., 2002). Although the nature of these B cell-T cell interactions is still not clarified, it is reasonable to think that the same types of B cells that generate cardinal autoantibodies are also providing activation signals to T cells that recognize cognate autoantigens. "
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    ABSTRACT: On the lupus-prone MRL-lpr/lpr (MRL-lpr) background, AM14 rheumatoid factor (RF) B cells are activated, differentiate into plasmablasts, and undergo somatic hypermutation outside of follicles. Using multiple strategies to impair T cells, we found that such AM14 B cell activation did not require T cells but could be modulated by them. In vitro, the signaling adaptor MyD88 is required for IgG anti-chromatin to stimulate AM14 B cell proliferation when T cells are absent. However, the roles of Toll-like receptors (TLRs) in AM14 B cell activation in vivo have not been investigated. We found that activation, expansion, and differentiation of AM14 B cells depended on MyD88; however, mice lacking either TLR7 or TLR9 displayed partial defects, indicating complex roles for these receptors. T cell-independent activation of certain autoreactive B cells, which gain stimuli via endogenous TLR ligands instead of T cells, may be the initial step in the generation of canonical autoantibodies.
    Immunity 09/2008; 29(2):249-60. DOI:10.1016/j.immuni.2008.06.009 · 21.56 Impact Factor
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    • "Our results are supported by previous studies indicating that systemic FK506 treatment of mice is able to decrease serum levels of anti-DNA antibodies (Sugiyama et al., 2004). Because the numbers of CD19 þ B cells are not significantly reduced in FK506- injected CD40L tg mice compared to the PBS-treated control group, it is possible that the reduced production of antinuclear antibodies could be a consequence of impaired Th function as T cells can provide help to B cells (Fields et al., 2005). Alternatively, FK506 may also be able to influence B cell function directly. "
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    ABSTRACT: Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.
    Journal of Investigative Dermatology 06/2006; 126(6):1307-15. DOI:10.1038/sj.jid.5700185 · 7.22 Impact Factor
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    ABSTRACT: To investigate the mechanism by which T regulatory (Treg) cells may control the early onset of autoimmunity, we have used an adoptive transfer model to track Treg, Th, and anti-chromatin B cell interactions in vivo. We show that anti-chromatin B cells secrete Abs by day 8 in vivo upon provision of undeviated, Th1- or Th2-type CD4+ T cell help, but this secretion is blocked by the coinjection of CD4+ CD25+ Treg cells. Although Treg cells do not interfere with the initial follicular entry or activation of Th or B cells at day 3, ICOS levels on Th cells are decreased. Furthermore, Treg cells must be administered during the initial phases of the Ab response to exert full suppression of autoantibody production. These studies indicate that CD25+ Treg cells act to inhibit the maturation, rather than the initiation, of autoantibody responses.
    The Journal of Immunology 11/2005; 175(7):4255-64. DOI:10.4049/jimmunol.175.7.4255 · 4.92 Impact Factor
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