Homeostatic regulation of CD8+ T cells by perforin

Millet

Proc. Natl. Acad. Sci. U.S.A.

et al. 2007

113

Whereas NF-B has potent antiapoptotic function in most cell types, it was reported that in pancreatic ␤ cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of ␤ cell NF-B in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of I B␣ in pancreatic ␤ cells (RIP-mI B␣ mice). ␤ cells of these mice were more susceptible to killing by TNF-␣ plus IFN-␥ but more resistant to IL-1␤ plus IFN-␥ than normal ␤ cells. Similar results were obtained with ␤ cells lacking I B kinase ␤, a protein kinase required for NF-B activation. Inhibition of ␤ cell NF-B accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4 ؉ T cells was accelerated in RIP-mI B␣/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-B is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-B in IL-1␤-stimulated ␤ cells.

Section: Discussionmentioning

confidence: 99%

NF-κB prevents β cell death and autoimmune diabetes in NOD mice

Millet

Proc. Natl. Acad. Sci. U.S.A.

et al. 2007

113

“…It has also been shown that abnormal cytotoxic cells may fail to provide appropriate apoptotic signals for removal of activated macrophages and T cells during the contraction stage of some immune responses leading to persistent expansion of T cells and macrophages secreting proinflammatory cytokines. 34,35,37 As a result of continuous stimulation with proinflammatory cytokines (most notably, interferon gamma (IFNg)), macrophages will become hemophagocytic. 33,38 Although familial cases of MAS in sJIA have not been reported, as in FHLH, sJIA/MAS patients may also have functional defects in the exosome degranulation pathway.…”

Section: Genetic Factors For Mas In Sjiamentioning

confidence: 99%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30 --40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro-and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

“…Despite a similar degree of graft-vs.-host disease and normal Fas-mediated apoptosis, pko T cells are able to expand to greater numbers in allogeneic SCID mice than cells taken from wild-type donors [16]. In addition, while wild-type mice show deletion of specific activated CD8 + cells after persistent LCMV infection or after injection with staphylococcal enterotoxin B, pko mice accumulate reactive T cells and die of immune-mediated damage [17,18]. Furthermore, perforin defects in young human patients with familial hemophagocytic lymphohistiocytosis result in splenomegaly, accumulation of activated macrophages and lymphocytes, defective CTL and NK cytotoxicity, and elevated levels of serum IFN-+ and TNF- § [19], symptoms suggestive of a chronic inflammatory response and failure of AICD among other things in the absence of perforin.…”

Section: Introductionmentioning

confidence: 99%

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

et al. 2003

Activation-induced cell death (AICD) is a phenomenon in which activated T cells undergo apoptosis upon restimulation. We are studying a form of AICD that can occur before cells become competent to die by Fas (hence "early" AICD) and which depends on the presence of perforin. Previous studies indicate that it does not occur through granule exocytosis but via some endogenous pathway. We here investigate a possible role for caspases. Caspase 3 -/-cells were protected, suggesting a role for caspase 3 in early AICD. After recrosslinking, caspase 3 activity could be detected in cell lysates between 3 and 12 h, and CD8 + T cells became annexin V-positive between 15 and 18 h. Blocking anti-Fas ligand antibody failed to inhibit death, and no processing of either caspase 8 or caspase 9 was detected in recrosslinked cells. Furthermore, T cells lacking functional caspase 9 continued to die in early AICD. Thus, perforin-dependent early AICD appears to require activation of caspase 3, but not caspases 8 or 9. As perforin has no intrinsic catalytic abilities, we propose that it releases some endogenous activity that can activate caspase 3.