CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+T cells

Abstract

The recessive mouse mutations lpr and gld create deficiencies in an interacting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-ligand (FasL), respectively, resulting in autoantibody production resembling human systemic lupus erythematosus. The mechanisms of self-tolerance affected by deficiency in either molecule are not established, but CD95 deficiency both in B cells and in CD4+ T cells recognizing major histocompatibility complex (MHC) class II molecules is required for autoimmunity in lpr mice. Here we track the outcome of in vivo interactions between B cells and CD4+ T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells from mice transgenic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive cells) were triggered into proliferation and antibody production upon interaction with antigen and HEL-specific CD4+ T cells. By contrast, B cells that had been chronically exposed to HEL during their development and carried desensitized surface immunoglobulin (sIg) antigen receptors (anergic cells) did not produce antibody but instead were eliminated in the presence of HEL-specific CD4+ T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4+ T cells and were triggered to proliferate. These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95.

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

“…[21][22][23] Our results show that mitogenstimulated, c-Myc-deficient B lymphocytes are more resistant to CD95-induced cell death, and express low surface levels of CD95 and CD95L when compared to control cells (Figure 4a and b). Noteworthy is the fact that c-Myc-deficient B cells express normal surface levels of activation markers like CD69 or CD25, showing that they are capable of receiving Same numbers of sorted B lymphocytes were activated with either anti-CD40 antibody (10 mg/ml) or anti-CD40 plus interleukin 4 (20 ng/ml).…”

“…[18][19][20] Anti-CD40 stimulation of B lymphocytes induces the surface expression of CD95 and makes them susceptible to cell death by this receptor. [21][22][23] Furthermore, addition of interleukin 4 to anti-CD40-activated B lymphocytes renders these cells more resistant to CD95-induced cell death. 24 Inactivation of c-myc gene in the germ line results in embryonic lethality at day 9.5.…”

Ex vivo generation of genetically modified dendritic cells for immunotherapy: implications of lymphocyte contamination

“…Both CD4 + and CD8 + T-cell-mediated killing of cognate APC populations including DCs, B cells, and macrophages has been reported in several studies [20][21][22][23][43][44][45] and was shown to be mediated via Fas ligand (FasL)-dependent 20,[46][47][48] or -independent mechanisms. 23,44 Similarly, CD8 + CTL-mediated elimination of transplanted neo-antigen-positive T cells and other hematopoietic cells has been previously demonstrated in vivo both in animal models [27][28][29] and humans.…”

Rheumatic diseases in an MRL strain of mice with a deficit in the functional Fas ligand

“…Up-regulation of Fas antigen expression was observed in the MRLIgZd mice on splenic IgM-and/or IgD-positive B cells. Considering that Fas expression is almost absent on proand pre-B cells (26), is positive on mature B cells, and increases after activation in normal mice (26,27), the numbers of activated B cells were increased in the MRL/gZd mice, possibly because they were able to elude FasiFas-L-mediated B cell elimination (6). These B cells may contribute to persistent autoantibody production and the development of hypergammaglobulinemia, as shown in Figure 9.…”

“…The ligand for Fas (Fas-L) is a member of the TNF family (2), and is produced by activated CD8+ T cells and, to a lesser extent, by CD4+ T cells, mainly T helper 1 (3). The binding of this molecule with the Fas antigen can induce apoptosis of activated CD4+ T cells, B cells, and macrophages (4)(5)(6). This FasFas-L system has recently been thought to play a critical role in inducing a peripheral, rather than central, role in immune tolerance (7).…”